{"gene":"CD8A","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1985,"finding":"CD8A (T8) encodes a transmembrane glycoprotein with an N-terminal immunoglobulin variable region-like domain; gene isolation and sequencing established it as a single-pass transmembrane protein defining a functional class of cytotoxic T lymphocytes.","method":"Gene transfer, subtractive hybridization, cDNA/genomic cloning, sequencing","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — original gene isolation with full sequence and domain characterization, foundational study","pmids":["3871356"],"is_preprint":false},{"year":1989,"finding":"CD8A (and CD4) associates with the T cell-specific protein-tyrosine kinase p56lck; the CD8/p56lck complex phosphorylates CD3 complex subunits (γ, δ, ε, and ζ chains) at tyrosine residues, linking CD8A to TCR signaling.","method":"Co-immunoprecipitation, in vitro and in vivo radiolabeling, 2D-PAGE, in vitro kinase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional kinase activity demonstrated, foundational discovery replicated widely","pmids":["2470098"],"is_preprint":false},{"year":1989,"finding":"CD8A binds to the α3 domain of MHC class I (HLA-A,B,C) molecules; a single amino acid at position 245 (alanine vs. valine) in the α3 domain determines CD8 binding, with valine abrogating binding.","method":"Cell-cell binding assay, site-directed mutagenesis of HLA alleles","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis identifying critical contact residue, strong mechanistic evidence","pmids":["2784196"],"is_preprint":false},{"year":1992,"finding":"The extracellular domain of human CD8α forms an immunoglobulin variable domain fold and associates as Fv-like homodimers; only the N-terminal 114 amino acids form the structured domain visible in crystal structure.","method":"X-ray crystallography at 2.6 Å resolution of soluble CD8α fragment expressed in CHO cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with refined atomic model","pmids":["1547508"],"is_preprint":false},{"year":1997,"finding":"Crystal structure of CD8αα homodimer in complex with HLA-A2/peptide at 2.7 Å: CD8αα binds one HLA-A2 molecule, contacting both the α2 and α3 domains of HLA-A2 and β2-microglobulin; a flexible loop of the α3 domain (residues 223–229) is clamped between the CDR-like loops of the two CD8α subunits; the binding mode precludes simultaneous binding of a second MHC molecule; no conformational change extends to the MHC/peptide surface.","method":"X-ray crystallography at 2.7 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with detailed interface analysis","pmids":["9177355"],"is_preprint":false},{"year":1999,"finding":"Galectin-1-induced apoptosis in human T cells proceeds via segregation of CD45 and CD3 into distinct membrane microdomains (blebs with externalized phosphatidylserine) while CD7 and CD43 cluster separately; CD8 is not listed among the direct participants in galectin-1-induced death signaling.","method":"Flow cytometry, confocal microscopy, receptor redistribution assay","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 — localization study; CD8A not identified as direct mediator, peripheral relevance","pmids":["10490978"],"is_preprint":false},{"year":2000,"finding":"Soluble HLA-G1 triggers apoptosis in activated CD8+ T cells through the CD95/CD95L (Fas/FasL) pathway; the apoptotic effect is dependent on interaction with CD8 molecules, as blocking CD8 with various anti-CD8 mAbs prevents cell death. sHLA-G1 enhances CD95L expression on activated CD8+ T cells.","method":"Blocking antibody experiments, Western blotting for CD95L, CD95-Fc competitive inhibition, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal blocking approaches in a single lab; CD8 ligation shown necessary for apoptosis induction","pmids":["10843658"],"is_preprint":false},{"year":2000,"finding":"CD8β palmitoylation at its cytoplasmic tail allows CD8αβ heterodimer (but not CD8αα homodimer) to partition into lipid rafts. Raft localization concentrates CD8αβ with p56lck (nearly exclusively in rafts), enables CD8-mediated cross-linking to activate p56lck in a compartment lacking the phosphatase CD45, and allows p56lck to phosphorylate CD3ζ in rafts, inducing TCR signaling. Deletion of the CD8β cytoplasmic domain abolishes raft localization and p56lck association.","method":"Lipid raft fractionation, co-immunoprecipitation, phosphorylation assays, cytoplasmic domain deletion mutants, T cell hybridoma transfection system","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in transfectant system with mutagenesis, multiple orthogonal methods, mechanistic chain established","pmids":["10925291"],"is_preprint":false},{"year":2001,"finding":"The nonclassical MHC class I molecule TL (thymus leukemia antigen) preferentially binds the CD8αα homodimer (not CD8αβ); TL tetramers specifically react with CD8αα-expressing cells including most intestinal intraepithelial lymphocytes. High-affinity CD8αα-TL binding modifies TCR-mediated responses to antigen presented by distinct MHC molecules, defining a novel regulatory mechanism distinct from classical coreceptor function.","method":"TL tetramer staining, binding assays, functional T cell response assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated with tetramers plus functional consequence shown, orthogonal to classical MHC-I binding","pmids":["11729321"],"is_preprint":false},{"year":2003,"finding":"ILT2 and ILT4 (inhibitory receptors) compete with CD8 for MHC class I binding at the α3 domain; surface plasmon resonance shows ILT2 binds classical MHCIs with Kd ~2–45 μM, binds HLA-G with 3–4 fold higher affinity than classical MHCI, and ILT2 binds with ~2–3 fold higher affinity than ILT4 to the same MHCI. ILT2/ILT4 effectively compete with CD8 for MHCI binding, suggesting ILT2 can modulate CD8+ T cell activation by blocking the CD8-MHC interaction.","method":"Surface plasmon resonance (SPR), competitive binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — quantitative SPR with defined affinities, competitive binding rigorously demonstrated","pmids":["12853576"],"is_preprint":false},{"year":2003,"finding":"Soluble classical HLA-A,-B,-C molecules (as well as sHLA-G1) induce apoptosis in both CD8+ T lymphocytes and CD8+ NK cells (which lack TCR) via CD8 ligation, leading to FasL upregulation, soluble FasL secretion, and Fas/sFasL-mediated cell death. Soluble HLA also inhibits EBV-specific CD8+ CTL cytotoxic activity through CD8 engagement.","method":"Apoptosis assays, FasL ELISA, blocking antibodies, purified soluble HLA molecules from serum and transfected cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (apoptosis + FasL measurement + CTL inhibition + CD8 blocking), single lab","pmids":["12594841"],"is_preprint":false},{"year":2003,"finding":"The cytoplasmic tails of CD8α (and CD4) associate with the N-terminus of Lck through a zinc-mediated 'zinc clasp' structure. NMR solution structures of CD8α-Lck-Zn2+ ternary complex show that the unstructured cytoplasmic tails of CD8α and the Lck N-terminus co-fold in the presence of zinc into compact heterodimeric domains. The dileucine motif required for CD4 endocytosis is masked by Lck in the CD4-Lck complex; CD8α forms a similar but structurally distinct zinc clasp.","method":"NMR spectroscopy, solution structure determination of ternary complexes","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with defined atomic interactions, zinc-dependency validated","pmids":["14500983"],"is_preprint":false},{"year":2007,"finding":"CD8αβ heterodimer raft localization in human T cells is driven by assembly of CD8α and CD8β extracellular regions (not palmitoylation of human CD8α or CD8β per se). Formation of the CD8αβ heterodimer itself induces raft association: a non-raft CD8β chain combined with a non-raft CD8α chain yields raft-localized CD8αβ. Two CD8α extracellular regions (as in CD8αα) appear to preclude raft localization. Arginines in the CD8β cytoplasmic domain also contribute to raft localization.","method":"Lipid raft fractionation, chimeric CD8 proteins, palmitoylation analysis, transfection of human CD8 constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic chimeric protein analysis with multiple mutants, mechanistic distinction from mouse CD8 established","pmids":["17341584"],"is_preprint":false},{"year":2007,"finding":"CD8αα homodimers fail to provide coreceptor function for a CD8-dependent TCR; only CD8αβ heterodimers support antigen-specific cytotoxicity and IFN-γ production for a high-avidity CD8-dependent TCR clone. In CD8β-deficient T cells, only CD8-independent TCRs remain functional, demonstrating that CD8 dependence is TCR-intrinsic and requires the CD8β chain.","method":"Retroviral TCR gene transfer into wild-type and CD8β-deficient primary mouse T cells, antibody blocking, cytotoxicity assays, IFN-γ production","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic reconstitution in primary cells with clear loss-of-function phenotype, reciprocal gain-of-function controls","pmids":["17506031"],"is_preprint":false},{"year":2013,"finding":"CEACAM5 (gp180) interacts directly with CD8α through its N-domain, and this interaction activates CD8-associated Lck. CEACAM5 is the only CEACAM family member that interacts with CD8α; glycosylation of the CEACAM5 N-domain is critical for CD8α binding affinity and Lck activation. CEACAM5-activated CD8+ T cells acquire suppressor function (inhibiting CD4+ T cell proliferation) in the presence of IL-15 or IL-7.","method":"Co-immunoprecipitation, domain deletion/glycosylation mutants, Lck kinase activity assay, T cell suppression assay","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 — pulldown with domain mapping and functional consequence (Lck activation + T cell suppression), single lab","pmids":["24104458"],"is_preprint":false},{"year":2013,"finding":"ADP-ribosylation of CD8β (on murine CD8+ T cells) by ART2.2 using extracellular NAD+ modifies specific epitopes of CD8β, impairs binding of OVA:MHC-I tetramers to CD8, and reduces CD8+ T cell-mediated cytotoxicity in vivo. The modification is strictly ART2.2-dependent (absent in ART2-deficient T cells) and is reversed by anti-ART2.2 single-domain antibodies.","method":"NAD+ treatment, anti-CD8β antibody binding assays, MHC-I tetramer binding, in vivo cytotoxicity assay, ART2-deficient mice","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — enzyme-dependent PTM demonstrated with functional consequence in vivo, single lab","pmids":["23575529"],"is_preprint":false},{"year":2022,"finding":"CD8α maintains peripheral CD8+ T cells in a physiologically quiescent state. Inducible deletion of CD8α causes both naïve and memory CD8+ T cells to spontaneously acquire activation phenotypes and die without antigen exposure. PILRα (paired immunoglobulin-like type 2 receptor alpha) was identified as a ligand for CD8α in both mice and humans; disruption of the CD8α-PILRα interaction breaks CD8+ T cell quiescence, defining a non-coreceptor function of CD8α in peripheral T cell homeostasis.","method":"Inducible CD8α knockout mice, flow cytometry phenotyping, co-immunoprecipitation/binding assays to identify PILRα as CD8α ligand, functional disruption experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with clear phenotype plus identification of binding partner, both mouse and human validation","pmids":["35617401"],"is_preprint":false}],"current_model":"CD8A encodes the CD8α chain, which functions as a co-receptor for MHC class I: its immunoglobulin V-like extracellular domain binds the α3 domain of MHC-I (crystal structure resolved at 2.7 Å), its cytoplasmic tail associates with the Src-family kinase p56lck via a zinc clasp structure to phosphorylate CD3ζ and initiate TCR signaling, with CD8αβ heterodimers (but not CD8αα homodimers) achieving superior coreceptor function through CD8β palmitoylation/raft localization in mice or heterodimer-driven raft association in humans; additionally, CD8αα binds the non-classical MHC-I molecule TL to modulate intestinal T cell responses, soluble MHC-I molecules can ligate CD8α to induce FasL-mediated apoptosis, CEACAM5 activates Lck through CD8α binding, ADP-ribosylation of CD8β impairs coreceptor function, and CD8α maintains peripheral T cell quiescence through interaction with PILRα."},"narrative":{"teleology":[{"year":1985,"claim":"Establishing the molecular identity of the CD8 co-receptor: cloning and sequencing of CD8A revealed a transmembrane glycoprotein with an Ig V-like domain, defining the gene product that marks cytotoxic T lymphocytes.","evidence":"Gene transfer, subtractive hybridization, cDNA/genomic cloning, and sequencing in T cell lines","pmids":["3871356"],"confidence":"High","gaps":["No binding partner or signaling function yet identified","Structure of the extracellular domain unknown"]},{"year":1989,"claim":"Two foundational functions were established simultaneously: CD8α binds the α3 domain of MHC class I (with a single residue at position 245 governing binding) and associates with p56Lck to phosphorylate CD3 subunits, linking CD8 to both antigen recognition and TCR signaling.","evidence":"Site-directed mutagenesis of HLA alleles with cell-cell binding assays; co-immunoprecipitation and in vitro kinase assays in T cells","pmids":["2784196","2470098"],"confidence":"High","gaps":["Structural basis of CD8–MHC interaction unresolved","Mechanism of CD8α–Lck association unknown at atomic level"]},{"year":1992,"claim":"Crystal structure of the CD8α extracellular domain revealed an Ig V-like fold that homodimerizes as an Fv-like unit, providing the first atomic framework for understanding its MHC-binding surface.","evidence":"X-ray crystallography at 2.6 Å of soluble CD8α expressed in CHO cells","pmids":["1547508"],"confidence":"High","gaps":["Structure of CD8αα in complex with MHC-I not yet available","No structural information on the CD8α–Lck interface"]},{"year":1997,"claim":"The co-crystal of CD8αα with HLA-A2/peptide at 2.7 Å resolved how CD8 engages MHC-I: the two CD8α subunits clamp a flexible loop of the α3 domain (residues 223–229) between their CDR-like loops, contacting both α2/α3 and β2m, with geometry that precludes binding a second MHC molecule.","evidence":"X-ray crystallography at 2.7 Å resolution","pmids":["9177355"],"confidence":"High","gaps":["No structure of CD8αβ heterodimer with MHC-I","Functional difference between CD8αα and CD8αβ coreceptor activity unexplained structurally"]},{"year":2000,"claim":"The functional superiority of CD8αβ over CD8αα was mechanistically explained: CD8β palmitoylation drives heterodimer partitioning into lipid rafts where Lck is concentrated and CD45 is excluded, enabling efficient CD3ζ phosphorylation—a compartmentalization mechanism absent in the homodimer.","evidence":"Lipid raft fractionation, co-immunoprecipitation, phosphorylation assays, and CD8β cytoplasmic domain deletion mutants in T cell hybridomas (murine system)","pmids":["10925291"],"confidence":"High","gaps":["Whether human CD8αβ uses the same palmitoylation-dependent mechanism was unresolved","Role of the CD8β extracellular domain in raft targeting not addressed"]},{"year":2001,"claim":"Discovery that CD8αα has a distinct ligand—the nonclassical MHC molecule TL—established a non-coreceptor function for the homodimer: CD8αα–TL binding on intestinal intraepithelial lymphocytes modulates TCR responses independently of classical MHC-I restriction.","evidence":"TL tetramer staining, binding assays, and functional T cell response assays","pmids":["11729321"],"confidence":"High","gaps":["Structural basis of CD8αα–TL recognition unknown at this point","Downstream signaling consequences of TL engagement unclear"]},{"year":2003,"claim":"Three advances deepened the mechanistic picture: (i) the CD8α–Lck zinc clasp structure was solved by NMR, showing zinc-dependent co-folding of unstructured tails; (ii) ILTs were shown to compete with CD8 for MHC-I α3 binding with quantified affinities; (iii) soluble MHC-I ligation of CD8 was shown to upregulate FasL and induce apoptosis in both CD8+ T and NK cells.","evidence":"NMR solution structure of CD8α–Lck–Zn²⁺ complex; SPR-based competitive binding; apoptosis and FasL assays with blocking antibodies","pmids":["14500983","12853576","12594841","10843658"],"confidence":"High","gaps":["Whether zinc clasp formation is regulated in vivo unknown","Physiological significance of soluble MHC–CD8 apoptotic signaling in immune regulation unclear"]},{"year":2007,"claim":"Species-specific mechanisms of CD8αβ raft targeting were delineated: in human T cells, heterodimer ectodomain assembly (not palmitoylation) drives raft localization, with CD8β cytoplasmic arginines contributing—contrasting the murine palmitoylation-dependent mechanism. Separately, genetic reconstitution confirmed that only CD8αβ (not CD8αα) provides coreceptor function for CD8-dependent TCRs.","evidence":"Chimeric CD8 protein analysis with lipid raft fractionation in human cells; retroviral TCR transfer into wild-type and CD8β-deficient primary mouse T cells","pmids":["17341584","17506031"],"confidence":"High","gaps":["Structural basis for why CD8αα ectodomains exclude raft partitioning unknown","No structure of the human CD8αβ heterodimer"]},{"year":2013,"claim":"Two modulatory inputs onto the CD8 coreceptor axis were identified: CEACAM5 binds CD8α via its glycosylated N-domain to activate Lck and generate suppressor CD8+ T cells, while ART2.2-mediated ADP-ribosylation of CD8β impairs MHC-I tetramer binding and cytotoxicity in vivo.","evidence":"Co-immunoprecipitation with domain/glycosylation mutants, Lck kinase and T cell suppression assays (CEACAM5); NAD+ treatment, tetramer binding, and in vivo cytotoxicity in ART2-deficient mice (ADP-ribosylation)","pmids":["24104458","23575529"],"confidence":"Medium","gaps":["CEACAM5–CD8α interaction validated only in one laboratory","Physiological relevance of ADP-ribosylation of CD8β to immune regulation in vivo needs broader confirmation","Structural basis of CEACAM5–CD8α binding unknown"]},{"year":2022,"claim":"A non-coreceptor homeostatic role for CD8α was established: inducible CD8α deletion causes spontaneous activation and death of naïve and memory CD8+ T cells, and PILRα was identified as a CD8α ligand whose disruption phenocopies this loss of quiescence—defining CD8α as a tonic quiescence signal independent of TCR-MHC interaction.","evidence":"Inducible CD8α knockout mice, flow cytometry phenotyping, co-immunoprecipitation identifying PILRα, functional disruption in mouse and human systems","pmids":["35617401"],"confidence":"High","gaps":["Signaling pathway downstream of CD8α–PILRα interaction not characterized","Whether PILRα competes with MHC-I for CD8α binding unknown","Relevance to human autoimmune or immunodeficiency phenotypes untested"]},{"year":null,"claim":"Key open questions include the structural basis of the CD8αβ heterodimer (no crystal or cryo-EM structure exists), how the CD8α–PILRα quiescence signal is transduced intracellularly, and whether the multiple non-coreceptor functions of CD8α (TL binding, CEACAM5 engagement, soluble MHC-induced apoptosis, PILRα-mediated quiescence) are integrated or context-exclusive.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of CD8αβ heterodimer","Intracellular signaling downstream of CD8α–PILRα unknown","Functional hierarchy among multiple CD8α ligands in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,7,11]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,4,7,8,13,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,11,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,10]}],"complexes":["CD8αβ heterodimer","CD8αα homodimer","CD8α–Lck zinc clasp complex","TCR–CD3–CD8 signaling complex"],"partners":["LCK","B2M","CEACAM5","PILRA","CD247","LILRB1"],"other_free_text":[]},"mechanistic_narrative":"CD8A encodes the α chain of the CD8 co-receptor, a single-pass transmembrane glycoprotein with an immunoglobulin V-like extracellular domain that binds the α3 domain of MHC class I molecules to enhance TCR signaling on cytotoxic T lymphocytes [PMID:3871356, PMID:2784196, PMID:9177355]. Its cytoplasmic tail recruits the Src-family kinase p56Lck through a zinc-dependent clasp structure, enabling Lck-mediated phosphorylation of CD3ζ and TCR signal transduction; superior coreceptor function requires the CD8αβ heterodimer, which partitions into lipid rafts—via CD8β palmitoylation in mice or heterodimer-driven ectodomain assembly in humans—concentrating Lck away from the phosphatase CD45 [PMID:2470098, PMID:14500983, PMID:10925291, PMID:17341584]. Beyond classical coreceptor activity, the CD8αα homodimer binds the nonclassical MHC molecule TL to modulate intestinal intraepithelial lymphocyte responses, and CD8α engagement by soluble MHC-I or CEACAM5 can trigger FasL-mediated apoptosis or Lck activation leading to suppressor T cell function, respectively [PMID:11729321, PMID:10843658, PMID:24104458]. CD8α also maintains peripheral T cell quiescence through interaction with PILRα; inducible loss of CD8α causes spontaneous activation and death of naïve and memory CD8+ T cells independently of antigen [PMID:35617401]."},"prefetch_data":{"uniprot":{"accession":"P01732","full_name":"T-cell surface glycoprotein CD8 alpha chain","aliases":["T-lymphocyte differentiation antigen T8/Leu-2"],"length_aa":235,"mass_kda":25.7,"function":"Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class I molecule:peptide complex. The antigens presented by class I peptides are derived from cytosolic proteins while class II derived from extracellular proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class I proteins presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of cytotoxic T-lymphocytes (CTLs). This mechanism enables CTLs to recognize and eliminate infected cells and tumor cells. In NK-cells, the presence of CD8A homodimers at the cell surface provides a survival mechanism allowing conjugation and lysis of multiple target cells. CD8A homodimer molecules also promote the survival and differentiation of activated lymphocytes into memory CD8 T-cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P01732/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD8A","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD8A","total_profiled":1310},"omim":[{"mim_id":"619558","title":"RAB39A, MEMBER RAS ONCOGENE FAMILY; RAB39A","url":"https://www.omim.org/entry/619558"},{"mim_id":"614983","title":"BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE 2; BATF2","url":"https://www.omim.org/entry/614983"},{"mim_id":"614664","title":"TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS-LIKE PROTEIN 4; TREML4","url":"https://www.omim.org/entry/614664"},{"mim_id":"612880","title":"SYNAPTOTAGMIN-LIKE 2; SYTL2","url":"https://www.omim.org/entry/612880"},{"mim_id":"612597","title":"CYTOTOXIC AND REGULATORY T-CELL MOLECULE; CRTAM","url":"https://www.omim.org/entry/612597"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":216.0}],"url":"https://www.proteinatlas.org/search/CD8A"},"hgnc":{"alias_symbol":["p32","CD8alpha"],"prev_symbol":["CD8"]},"alphafold":{"accession":"P01732","domains":[{"cath_id":"2.60.40.10","chopping":"22-132","consensus_level":"high","plddt":93.597,"start":22,"end":132},{"cath_id":"1.20.5","chopping":"180-214","consensus_level":"medium","plddt":84.5797,"start":180,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01732","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01732-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01732-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD8A","jax_strain_url":"https://www.jax.org/strain/search?query=CD8A"},"sequence":{"accession":"P01732","fasta_url":"https://rest.uniprot.org/uniprotkb/P01732.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01732/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01732"}},"corpus_meta":[{"pmid":"31043744","id":"PMC_31043744","title":"CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31043744","citation_count":2257,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31207603","id":"PMC_31207603","title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31207603","citation_count":1241,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34253904","id":"PMC_34253904","title":"CD8+ T cell differentiation and dysfunction in cancer.","date":"2021","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34253904","citation_count":770,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33981085","id":"PMC_33981085","title":"CD8+ T cell metabolism in infection and cancer.","date":"2021","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33981085","citation_count":499,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32624246","id":"PMC_32624246","title":"The Roles of CD8+ T Cell Subsets in Antitumor Immunity.","date":"2020","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32624246","citation_count":482,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14512632","id":"PMC_14512632","title":"Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14512632","citation_count":422,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29379213","id":"PMC_29379213","title":"Epigenetic control of CD8+ T cell differentiation.","date":"2018","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29379213","citation_count":405,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34354714","id":"PMC_34354714","title":"CD8+ T Cell Exhaustion in Cancer.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34354714","citation_count":377,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9177355","id":"PMC_9177355","title":"Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9177355","citation_count":376,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27798602","id":"PMC_27798602","title":"S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27798602","citation_count":346,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30989321","id":"PMC_30989321","title":"CD8+ T cell exhaustion.","date":"2019","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/30989321","citation_count":243,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32231301","id":"PMC_32231301","title":"Sestrins induce natural killer function in senescent-like CD8+ T cells.","date":"2020","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32231301","citation_count":199,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29326266","id":"PMC_29326266","title":"The epigenetic control of stemness in CD8+ T cell fate commitment.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29326266","citation_count":188,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36302380","id":"PMC_36302380","title":"Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/36302380","citation_count":169,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29849151","id":"PMC_29849151","title":"Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29849151","citation_count":169,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28894104","id":"PMC_28894104","title":"NFATc1 controls the cytotoxicity of CD8+ T cells.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28894104","citation_count":167,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28806909","id":"PMC_28806909","title":"Tumor-derived exosomes induce CD8+ T cell suppressors.","date":"2017","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28806909","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33277233","id":"PMC_33277233","title":"Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8+ T Cells.","date":"2020","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/33277233","citation_count":155,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10925291","id":"PMC_10925291","title":"Essential role of CD8 palmitoylation in CD8 coreceptor function.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10925291","citation_count":153,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15829311","id":"PMC_15829311","title":"Characterisation of salmon and trout CD8alpha and CD8beta.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15829311","citation_count":132,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21352850","id":"PMC_21352850","title":"The expression of CD8α discriminates distinct T cell subsets in teleost fish.","date":"2011","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21352850","citation_count":131,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36584935","id":"PMC_36584935","title":"CD8+ T cell exhaustion and cancer immunotherapy.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/36584935","citation_count":126,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29400704","id":"PMC_29400704","title":"Functions of NKG2D in CD8+ T cells: an opportunity for immunotherapy.","date":"2018","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29400704","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23070399","id":"PMC_23070399","title":"Notch signaling regulates PD-1 expression during CD8(+) T-cell activation.","date":"2012","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23070399","citation_count":115,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27829149","id":"PMC_27829149","title":"CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27829149","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10449161","id":"PMC_10449161","title":"Role of CD8alpha+ and CD8alpha- dendritic cells in the induction of primary immune responses in vivo.","date":"1999","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/10449161","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32989328","id":"PMC_32989328","title":"BATF3 programs CD8+ T cell memory.","date":"2020","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32989328","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29441071","id":"PMC_29441071","title":"Regulation of CD8+ T Cells and Antitumor Immunity by Notch Signaling.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29441071","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34462326","id":"PMC_34462326","title":"CXCR6 is required for antitumor efficacy of intratumoral CD8+ T cell.","date":"2021","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34462326","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33383733","id":"PMC_33383733","title":"CD8+ T Cells in Atherosclerosis.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33383733","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25577280","id":"PMC_25577280","title":"Molecular mechanisms of CD8(+) T cell trafficking and localization.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/25577280","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26904023","id":"PMC_26904023","title":"Starved and Asphyxiated: How Can CD8(+) T Cells within a Tumor Microenvironment Prevent Tumor Progression.","date":"2016","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26904023","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30659052","id":"PMC_30659052","title":"Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/30659052","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34484208","id":"PMC_34484208","title":"CD8+ Regulatory T Cell - A Mystery to Be Revealed.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34484208","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33306960","id":"PMC_33306960","title":"The Identity of Human Tissue-Emigrant CD8+ T Cells.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33306960","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31204281","id":"PMC_31204281","title":"Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells.","date":"2019","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31204281","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31754392","id":"PMC_31754392","title":"CD4+ and CD8a+ PET imaging predicts response to novel PD-1 checkpoint inhibitor: studies of Sym021 in syngeneic mouse cancer models.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31754392","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22862959","id":"PMC_22862959","title":"Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium.","date":"2012","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/22862959","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27899443","id":"PMC_27899443","title":"RAB43 facilitates cross-presentation of cell-associated antigens by CD8α+ dendritic cells.","date":"2016","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27899443","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28123871","id":"PMC_28123871","title":"Hypoxia and antitumor CD8+ T cells: An incompatible alliance?","date":"2016","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/28123871","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31744753","id":"PMC_31744753","title":"The C1q Receptors: Focus on gC1qR/p33 (C1qBP, p32, HABP-1)1.","date":"2019","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31744753","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22802630","id":"PMC_22802630","title":"Cross-dressed CD8α+/CD103+ dendritic cells prime CD8+ T cells following vaccination.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22802630","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29358941","id":"PMC_29358941","title":"Methods of Controlling Invasive Fungal Infections Using CD8+ T Cells.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29358941","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18406591","id":"PMC_18406591","title":"Emerging concepts in CD8(+) T regulatory cells.","date":"2008","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18406591","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19497720","id":"PMC_19497720","title":"Diversity in CD8(+) T cell differentiation.","date":"2009","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19497720","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37582972","id":"PMC_37582972","title":"Regulation of CD8+ T memory and exhaustion by the mTOR signals.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37582972","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30578304","id":"PMC_30578304","title":"Costimulation through TLR2 Drives Polyfunctional CD8+ T Cell Responses.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30578304","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11745359","id":"PMC_11745359","title":"Mouse pre-immunocytes as non-proliferating multipotent precursors of macrophages, interferon-producing cells, CD8alpha(+) and CD8alpha(-) dendritic cells.","date":"2001","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11745359","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19941111","id":"PMC_19941111","title":"CD8+, CD8-, and plasmacytoid dendritic cell generation in vitro using flt3 ligand.","date":"2010","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/19941111","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28662970","id":"PMC_28662970","title":"Molecular Dissection of CD8+ T-Cell Dysfunction.","date":"2017","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28662970","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33795809","id":"PMC_33795809","title":"CD8+ T cells inhibit metastasis and CXCL4 regulates its function.","date":"2021","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33795809","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16220536","id":"PMC_16220536","title":"Properties of murine (CD8+)CD27- T cells.","date":"2005","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16220536","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35397197","id":"PMC_35397197","title":"Epigenetic quantification of immunosenescent CD8+ TEMRA cells in human blood.","date":"2022","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/35397197","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12649155","id":"PMC_12649155","title":"CD8alpha+ mouse spleen dendritic cells do not originate from the CD8alpha- dendritic cell subset.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12649155","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35622904","id":"PMC_35622904","title":"Rgs16 promotes antitumor CD8+ T cell exhaustion.","date":"2022","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35622904","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25909887","id":"PMC_25909887","title":"Chaperone-like protein p32 regulates ULK1 stability and autophagy.","date":"2015","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/25909887","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22147811","id":"PMC_22147811","title":"Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8α- dendritic cell subset.","date":"2011","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/22147811","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10910289","id":"PMC_10910289","title":"Preferential induction of Th1 responses by functionally mature hepatic (CD8alpha- and CD8alpha+) dendritic cells: association with conversion from liver transplant tolerance to acute rejection.","date":"2000","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/10910289","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33801203","id":"PMC_33801203","title":"CD8+ T Cell Responses during HCV Infection and HCC.","date":"2021","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33801203","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33123174","id":"PMC_33123174","title":"Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33123174","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33648987","id":"PMC_33648987","title":"CD8+ T-Cell Memory: The Why, the When, and the How.","date":"2021","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/33648987","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17341584","id":"PMC_17341584","title":"CD8 Raft localization is induced by its assembly into CD8alpha beta heterodimers, Not CD8alpha alpha homodimers.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17341584","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29891555","id":"PMC_29891555","title":"Cysteine-Reactive Free ISG15 Generates IL-1β-Producing CD8α+ Dendritic Cells at the Site of Infection.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29891555","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29981781","id":"PMC_29981781","title":"Expression of CCR6 and CXCR6 by Gut-Derived CD4+/CD8α+ T-Regulatory Cells, Which Are Decreased in Blood Samples From Patients With Inflammatory Bowel Diseases.","date":"2018","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/29981781","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27484289","id":"PMC_27484289","title":"MicroRNA-491 regulates the proliferation and apoptosis of CD8(+) T cells.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27484289","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17964665","id":"PMC_17964665","title":"Unique functions of splenic CD8alpha+ dendritic cells during infection with intracellular pathogens.","date":"2007","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/17964665","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28096804","id":"PMC_28096804","title":"Divide, Conquer, and Sense: CD8+CD28- T Cells in Perspective.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28096804","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39266501","id":"PMC_39266501","title":"IL-4 drives exhaustion of CD8+ CART cells.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39266501","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34923638","id":"PMC_34923638","title":"Epigenetics and CD8+ T cell memory.","date":"2021","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/34923638","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34411293","id":"PMC_34411293","title":"IL-33 activates mTORC1 and modulates glycolytic metabolism in CD8+ T cells.","date":"2021","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34411293","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32141029","id":"PMC_32141029","title":"Prevalence of CD8+ cytotoxic lymphocytes in human neoplasms.","date":"2020","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/32141029","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39317187","id":"PMC_39317187","title":"CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway.","date":"2024","source":"Cell genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39317187","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36897779","id":"PMC_36897779","title":"KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations in humans.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36897779","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9855049","id":"PMC_9855049","title":"CD4+ CD8+ and CD8alpha+ beta- T lymphocytes in human small intestinal lamina propria.","date":"1998","source":"European journal of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/9855049","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17506031","id":"PMC_17506031","title":"CD8alpha/alpha homodimers fail to function as co-receptor for a CD8-dependent TCR.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17506031","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24746816","id":"PMC_24746816","title":"Impaired p32 regulation caused by the lymphoma-prone RECQ4 mutation drives mitochondrial dysfunction.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24746816","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38763950","id":"PMC_38763950","title":"DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism.","date":"2024","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38763950","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38169635","id":"PMC_38169635","title":"p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38169635","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39912921","id":"PMC_39912921","title":"Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8α+ lymphocytes.","date":"2025","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39912921","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35753961","id":"PMC_35753961","title":"Arming a killer: mitochondrial regulation of CD8+ T cell cytotoxicity.","date":"2022","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35753961","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33867272","id":"PMC_33867272","title":"How metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications.","date":"2021","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33867272","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24104458","id":"PMC_24104458","title":"Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.","date":"2013","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24104458","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30420437","id":"PMC_30420437","title":"CD8α+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30420437","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23575529","id":"PMC_23575529","title":"CD8-β ADP-ribosylation affects CD8(+) T-cell function.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23575529","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34815204","id":"PMC_34815204","title":"Antimetastatic defense by CD8+ T cells.","date":"2021","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34815204","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37558570","id":"PMC_37558570","title":"Factors contributing to the potency of CD8+ T cells.","date":"2023","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37558570","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35617401","id":"PMC_35617401","title":"The CD8α-PILRα interaction maintains CD8+ T cell quiescence.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35617401","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36275711","id":"PMC_36275711","title":"Lipids for CD8+ TILs: Beneficial or harmful?","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36275711","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9678487","id":"PMC_9678487","title":"Physical association between the EBV protein EBNA-1 and P32/TAP/hyaluronectin.","date":"1998","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/9678487","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30135685","id":"PMC_30135685","title":"Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30135685","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39342365","id":"PMC_39342365","title":"Focusing on CD8+ T-cell phenotypes: improving solid tumor therapy.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39342365","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24505360","id":"PMC_24505360","title":"DNA methylation and regulation of the CD8A after duck hepatitis virus type 1 infection.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24505360","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36653953","id":"PMC_36653953","title":"Shaping immunity for life: Layered development of CD8+ T cells.","date":"2023","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/36653953","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33459125","id":"PMC_33459125","title":"Lipophagy confers a key metabolic advantage that ensures protective CD8A T-cell responses against HIV-1.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33459125","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36690860","id":"PMC_36690860","title":"CD8+ lymphocytes do not impact SIV reservoir establishment under ART.","date":"2023","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36690860","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41034337","id":"PMC_41034337","title":"Regulators of CD8+ T cell exhaustion.","date":"2025","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41034337","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39762445","id":"PMC_39762445","title":"The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to control antitumor immunity.","date":"2025","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39762445","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29465311","id":"PMC_29465311","title":"p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29465311","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23878314","id":"PMC_23878314","title":"CCL22-producing CD8α- myeloid dendritic cells mediate regulatory T cell recruitment in response to G-CSF treatment.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23878314","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36353619","id":"PMC_36353619","title":"Single-cell transcriptomics of human gut T cells identifies cytotoxic CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36353619","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18156204","id":"PMC_18156204","title":"Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.","date":"2007","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18156204","citation_count":927,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10444591","id":"PMC_10444591","title":"Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10444591","citation_count":914,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9790534","id":"PMC_9790534","title":"The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9790534","citation_count":701,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9804427","id":"PMC_9804427","title":"Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9804427","citation_count":585,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21430066","id":"PMC_21430066","title":"Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21430066","citation_count":490,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2470098","id":"PMC_2470098","title":"The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex.","date":"1989","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2470098","citation_count":464,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12853576","id":"PMC_12853576","title":"Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12853576","citation_count":448,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10843658","id":"PMC_10843658","title":"Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10843658","citation_count":366,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3871356","id":"PMC_3871356","title":"The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes.","date":"1985","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3871356","citation_count":320,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25894502","id":"PMC_25894502","title":"COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25894502","citation_count":300,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12594841","id":"PMC_12594841","title":"Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation.","date":"2003","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12594841","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12899833","id":"PMC_12899833","title":"Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms.","date":"2003","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12899833","citation_count":287,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11102443","id":"PMC_11102443","title":"Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11102443","citation_count":274,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10490978","id":"PMC_10490978","title":"Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10490978","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2493728","id":"PMC_2493728","title":"Molecular biology and function of CD4 and CD8.","date":"1989","source":"Advances in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2493728","citation_count":257,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2784196","id":"PMC_2784196","title":"Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8.","date":"1989","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2784196","citation_count":252,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1547508","id":"PMC_1547508","title":"Crystal structure of a soluble form of the human T cell coreceptor CD8 at 2.6 A resolution.","date":"1992","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1547508","citation_count":246,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18483277","id":"PMC_18483277","title":"Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18483277","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18695005","id":"PMC_18695005","title":"Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection.","date":"2008","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18695005","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14500983","id":"PMC_14500983","title":"A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14500983","citation_count":202,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11729321","id":"PMC_11729321","title":"T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11729321","citation_count":198,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18650384","id":"PMC_18650384","title":"Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18650384","citation_count":193,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21948982","id":"PMC_21948982","title":"Cutting edge: expression of XCR1 defines mouse lymphoid-tissue resident and migratory dendritic cells of the CD8α+ type.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21948982","citation_count":180,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18398508","id":"PMC_18398508","title":"Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection.","date":"2008","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/18398508","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43997,"output_tokens":1940,"usd":0.080546},"stage2":{"model":"claude-opus-4-6","input_tokens":5447,"output_tokens":2032,"usd":0.117053},"total_usd":0.500338,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":56596,"output_tokens":4579,"usd":0.119236},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8542,"output_tokens":3185,"usd":0.183503}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of CD8αα homodimer bound to HLA-A2 at 2.7 Å resolution revealed that CD8αα binds one HLA-A2/peptide molecule by interfacing with the α2 and α3 domains of HLA-A2 and contacting β2-microglobulin; a flexible loop of the α3 domain (residues 223-229) is clamped between the CDR-like loops of the two CD8 subunits in an antibody-antigen-like interaction, and the binding is consistent with an avidity-based contribution to TCR-peptide-MHC interactions.\",\n      \"method\": \"X-ray crystallography at 2.7 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with direct structural validation of binding interface\",\n      \"pmids\": [\"9177355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD8β is palmitoylated at its cytoplasmic tail, enabling CD8αβ heterodimers (but not CD8αα homodimers) to partition into lipid rafts; raft localization concentrates CD8αβ with the src kinase p56lck (which is excluded from CD45-containing regions), enabling CD8-mediated cross-linking to activate p56lck, which then phosphorylates CD3ζ in rafts to initiate TCR signaling and T cell activation.\",\n      \"method\": \"CD8 transfectants in T cell hybridomas, lipid raft fractionation, palmitoylation assay, p56lck activation assay, cytoplasmic domain deletion mutants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (palmitoylation, raft fractionation, mutagenesis, kinase activation) in a single rigorous study\",\n      \"pmids\": [\"10925291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"For human CD8, raft localization is determined by assembly of the CD8αβ heterodimer through interaction of the extracellular regions of CD8α and CD8β, not by palmitoylation per se; two CD8α extracellular regions (as in CD8αα) preclude raft localization, whereas chimeric constructs showed that heterodimer formation and raft association are intimately linked.\",\n      \"method\": \"Chimeric CD8 constructs, lipid raft fractionation, palmitoylation assay in human T cells\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chimeric protein mutagenesis plus biochemical fractionation with rigorous controls\",\n      \"pmids\": [\"17341584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD8αα homodimers fail to provide co-receptor function for a CD8-dependent TCR: retroviral gene transfer of a CD8-dependent TCR into CD8β-deficient primary T cells (which express only CD8αα) abolished antigen-specific cytotoxicity, demonstrating that the CD8β chain is required for co-receptor function of high-avidity TCRs.\",\n      \"method\": \"Retroviral gene transfer, CD8β-deficient mouse T cells, cytotoxicity assay, antibody blocking\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function (CD8β KO) with clear functional readout replicated with multiple TCR clones\",\n      \"pmids\": [\"17506031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADP-ribosylation of CD8β by ART2.2 (using extracellular NAD+) at arginine residues on the extracellular domain interferes with MHC-I tetramer binding to CD8αβ and reduces CD8+ T cell-mediated cytotoxicity in vivo, demonstrating that this post-translational modification regulates CD8 co-receptor function.\",\n      \"method\": \"In vitro NAD+ treatment, ART2-deficient mice, anti-CD8β antibody epitope blocking, OVA:MHC-I tetramer binding assay, in vivo cytotoxicity assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO (ART2-deficient) plus in vitro and in vivo functional assays with defined mechanistic readout\",\n      \"pmids\": [\"23575529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM5 (gp180) binds CD8α through its N domain in a glycosylation-dependent manner; this interaction activates CD8-associated Lck, and CEACAM5-activated CD8+ T cells acquire suppressor function capable of inhibiting CD4+ T cell proliferation in vitro in the presence of IL-15 or IL-7.\",\n      \"method\": \"Co-immunoprecipitation, mAb competition, N-domain deletion mutants, deglycosylation, Lck kinase activation assay, in vitro suppression assay\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods in single lab; direct mechanistic chain from binding to Lck activation to functional outcome\",\n      \"pmids\": [\"24104458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD8α maintains CD8+ T cells (both naïve and memory) in a physiologically quiescent state in peripheral lymphoid organs; inducible deletion of CD8α caused spontaneous activation and death of CD8+ T cells without antigen exposure. PILRα was identified as a ligand for CD8α in both mice and humans, and disruption of the CD8α-PILRα interaction broke CD8+ T cell quiescence.\",\n      \"method\": \"Inducible CD8α deletion mouse model, ligand identification by binding screen, PILRα-CD8α interaction disruption, flow cytometry of activation phenotype\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with clear cellular phenotype plus identification of binding partner in two species; published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"35617401\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD8A encodes the CD8α chain which functions as a TCR co-receptor by binding MHC class I molecules (via a structurally defined interaction with the α2/α3 domains of HLA and β2-microglobulin), recruiting and activating p56lck in lipid rafts (a process requiring CD8αβ heterodimer formation and CD8β palmitoylation) to phosphorylate CD3ζ and initiate TCR signaling; additionally, CD8α engages PILRα on adjacent cells to maintain peripheral CD8+ T cell quiescence, while the CD8β chain is specifically required for co-receptor function of high-avidity TCRs, and ADP-ribosylation of CD8β by ART2.2 can suppress co-receptor activity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify papers and extract mechanistic discoveries about CD8A (the canonical CD8α protein).\n\n**Key classifications:**\n- Papers about CD8A protein function: KEEP\n- Papers about CD8+ T cell biology (but not specifically CD8A protein mechanism): EXCLUDE (expression/cell biology reviews)\n- Papers about p32/C1QBP: EXCLUDE (alias collision - different gene)\n- Papers about CD8α+ dendritic cell subsets (using CD8α as a marker, not studying CD8A protein mechanism): EXCLUDE unless they reveal CD8A mechanism\n- Papers revealing direct molecular mechanisms of CD8A: KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1985,\n      \"finding\": \"CD8A (T8) encodes a transmembrane glycoprotein with an N-terminal immunoglobulin variable region-like domain; gene isolation and sequencing established it as a single-pass transmembrane protein defining a functional class of cytotoxic T lymphocytes.\",\n      \"method\": \"Gene transfer, subtractive hybridization, cDNA/genomic cloning, sequencing\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original gene isolation with full sequence and domain characterization, foundational study\",\n      \"pmids\": [\"3871356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD8A (and CD4) associates with the T cell-specific protein-tyrosine kinase p56lck; the CD8/p56lck complex phosphorylates CD3 complex subunits (γ, δ, ε, and ζ chains) at tyrosine residues, linking CD8A to TCR signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo radiolabeling, 2D-PAGE, in vitro kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional kinase activity demonstrated, foundational discovery replicated widely\",\n      \"pmids\": [\"2470098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD8A binds to the α3 domain of MHC class I (HLA-A,B,C) molecules; a single amino acid at position 245 (alanine vs. valine) in the α3 domain determines CD8 binding, with valine abrogating binding.\",\n      \"method\": \"Cell-cell binding assay, site-directed mutagenesis of HLA alleles\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis identifying critical contact residue, strong mechanistic evidence\",\n      \"pmids\": [\"2784196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The extracellular domain of human CD8α forms an immunoglobulin variable domain fold and associates as Fv-like homodimers; only the N-terminal 114 amino acids form the structured domain visible in crystal structure.\",\n      \"method\": \"X-ray crystallography at 2.6 Å resolution of soluble CD8α fragment expressed in CHO cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with refined atomic model\",\n      \"pmids\": [\"1547508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of CD8αα homodimer in complex with HLA-A2/peptide at 2.7 Å: CD8αα binds one HLA-A2 molecule, contacting both the α2 and α3 domains of HLA-A2 and β2-microglobulin; a flexible loop of the α3 domain (residues 223–229) is clamped between the CDR-like loops of the two CD8α subunits; the binding mode precludes simultaneous binding of a second MHC molecule; no conformational change extends to the MHC/peptide surface.\",\n      \"method\": \"X-ray crystallography at 2.7 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with detailed interface analysis\",\n      \"pmids\": [\"9177355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Galectin-1-induced apoptosis in human T cells proceeds via segregation of CD45 and CD3 into distinct membrane microdomains (blebs with externalized phosphatidylserine) while CD7 and CD43 cluster separately; CD8 is not listed among the direct participants in galectin-1-induced death signaling.\",\n      \"method\": \"Flow cytometry, confocal microscopy, receptor redistribution assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization study; CD8A not identified as direct mediator, peripheral relevance\",\n      \"pmids\": [\"10490978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Soluble HLA-G1 triggers apoptosis in activated CD8+ T cells through the CD95/CD95L (Fas/FasL) pathway; the apoptotic effect is dependent on interaction with CD8 molecules, as blocking CD8 with various anti-CD8 mAbs prevents cell death. sHLA-G1 enhances CD95L expression on activated CD8+ T cells.\",\n      \"method\": \"Blocking antibody experiments, Western blotting for CD95L, CD95-Fc competitive inhibition, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal blocking approaches in a single lab; CD8 ligation shown necessary for apoptosis induction\",\n      \"pmids\": [\"10843658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD8β palmitoylation at its cytoplasmic tail allows CD8αβ heterodimer (but not CD8αα homodimer) to partition into lipid rafts. Raft localization concentrates CD8αβ with p56lck (nearly exclusively in rafts), enables CD8-mediated cross-linking to activate p56lck in a compartment lacking the phosphatase CD45, and allows p56lck to phosphorylate CD3ζ in rafts, inducing TCR signaling. Deletion of the CD8β cytoplasmic domain abolishes raft localization and p56lck association.\",\n      \"method\": \"Lipid raft fractionation, co-immunoprecipitation, phosphorylation assays, cytoplasmic domain deletion mutants, T cell hybridoma transfection system\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in transfectant system with mutagenesis, multiple orthogonal methods, mechanistic chain established\",\n      \"pmids\": [\"10925291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The nonclassical MHC class I molecule TL (thymus leukemia antigen) preferentially binds the CD8αα homodimer (not CD8αβ); TL tetramers specifically react with CD8αα-expressing cells including most intestinal intraepithelial lymphocytes. High-affinity CD8αα-TL binding modifies TCR-mediated responses to antigen presented by distinct MHC molecules, defining a novel regulatory mechanism distinct from classical coreceptor function.\",\n      \"method\": \"TL tetramer staining, binding assays, functional T cell response assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated with tetramers plus functional consequence shown, orthogonal to classical MHC-I binding\",\n      \"pmids\": [\"11729321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ILT2 and ILT4 (inhibitory receptors) compete with CD8 for MHC class I binding at the α3 domain; surface plasmon resonance shows ILT2 binds classical MHCIs with Kd ~2–45 μM, binds HLA-G with 3–4 fold higher affinity than classical MHCI, and ILT2 binds with ~2–3 fold higher affinity than ILT4 to the same MHCI. ILT2/ILT4 effectively compete with CD8 for MHCI binding, suggesting ILT2 can modulate CD8+ T cell activation by blocking the CD8-MHC interaction.\",\n      \"method\": \"Surface plasmon resonance (SPR), competitive binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative SPR with defined affinities, competitive binding rigorously demonstrated\",\n      \"pmids\": [\"12853576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Soluble classical HLA-A,-B,-C molecules (as well as sHLA-G1) induce apoptosis in both CD8+ T lymphocytes and CD8+ NK cells (which lack TCR) via CD8 ligation, leading to FasL upregulation, soluble FasL secretion, and Fas/sFasL-mediated cell death. Soluble HLA also inhibits EBV-specific CD8+ CTL cytotoxic activity through CD8 engagement.\",\n      \"method\": \"Apoptosis assays, FasL ELISA, blocking antibodies, purified soluble HLA molecules from serum and transfected cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (apoptosis + FasL measurement + CTL inhibition + CD8 blocking), single lab\",\n      \"pmids\": [\"12594841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytoplasmic tails of CD8α (and CD4) associate with the N-terminus of Lck through a zinc-mediated 'zinc clasp' structure. NMR solution structures of CD8α-Lck-Zn2+ ternary complex show that the unstructured cytoplasmic tails of CD8α and the Lck N-terminus co-fold in the presence of zinc into compact heterodimeric domains. The dileucine motif required for CD4 endocytosis is masked by Lck in the CD4-Lck complex; CD8α forms a similar but structurally distinct zinc clasp.\",\n      \"method\": \"NMR spectroscopy, solution structure determination of ternary complexes\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with defined atomic interactions, zinc-dependency validated\",\n      \"pmids\": [\"14500983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD8αβ heterodimer raft localization in human T cells is driven by assembly of CD8α and CD8β extracellular regions (not palmitoylation of human CD8α or CD8β per se). Formation of the CD8αβ heterodimer itself induces raft association: a non-raft CD8β chain combined with a non-raft CD8α chain yields raft-localized CD8αβ. Two CD8α extracellular regions (as in CD8αα) appear to preclude raft localization. Arginines in the CD8β cytoplasmic domain also contribute to raft localization.\",\n      \"method\": \"Lipid raft fractionation, chimeric CD8 proteins, palmitoylation analysis, transfection of human CD8 constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic chimeric protein analysis with multiple mutants, mechanistic distinction from mouse CD8 established\",\n      \"pmids\": [\"17341584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD8αα homodimers fail to provide coreceptor function for a CD8-dependent TCR; only CD8αβ heterodimers support antigen-specific cytotoxicity and IFN-γ production for a high-avidity CD8-dependent TCR clone. In CD8β-deficient T cells, only CD8-independent TCRs remain functional, demonstrating that CD8 dependence is TCR-intrinsic and requires the CD8β chain.\",\n      \"method\": \"Retroviral TCR gene transfer into wild-type and CD8β-deficient primary mouse T cells, antibody blocking, cytotoxicity assays, IFN-γ production\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic reconstitution in primary cells with clear loss-of-function phenotype, reciprocal gain-of-function controls\",\n      \"pmids\": [\"17506031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM5 (gp180) interacts directly with CD8α through its N-domain, and this interaction activates CD8-associated Lck. CEACAM5 is the only CEACAM family member that interacts with CD8α; glycosylation of the CEACAM5 N-domain is critical for CD8α binding affinity and Lck activation. CEACAM5-activated CD8+ T cells acquire suppressor function (inhibiting CD4+ T cell proliferation) in the presence of IL-15 or IL-7.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/glycosylation mutants, Lck kinase activity assay, T cell suppression assay\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulldown with domain mapping and functional consequence (Lck activation + T cell suppression), single lab\",\n      \"pmids\": [\"24104458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADP-ribosylation of CD8β (on murine CD8+ T cells) by ART2.2 using extracellular NAD+ modifies specific epitopes of CD8β, impairs binding of OVA:MHC-I tetramers to CD8, and reduces CD8+ T cell-mediated cytotoxicity in vivo. The modification is strictly ART2.2-dependent (absent in ART2-deficient T cells) and is reversed by anti-ART2.2 single-domain antibodies.\",\n      \"method\": \"NAD+ treatment, anti-CD8β antibody binding assays, MHC-I tetramer binding, in vivo cytotoxicity assay, ART2-deficient mice\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzyme-dependent PTM demonstrated with functional consequence in vivo, single lab\",\n      \"pmids\": [\"23575529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD8α maintains peripheral CD8+ T cells in a physiologically quiescent state. Inducible deletion of CD8α causes both naïve and memory CD8+ T cells to spontaneously acquire activation phenotypes and die without antigen exposure. PILRα (paired immunoglobulin-like type 2 receptor alpha) was identified as a ligand for CD8α in both mice and humans; disruption of the CD8α-PILRα interaction breaks CD8+ T cell quiescence, defining a non-coreceptor function of CD8α in peripheral T cell homeostasis.\",\n      \"method\": \"Inducible CD8α knockout mice, flow cytometry phenotyping, co-immunoprecipitation/binding assays to identify PILRα as CD8α ligand, functional disruption experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with clear phenotype plus identification of binding partner, both mouse and human validation\",\n      \"pmids\": [\"35617401\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD8A encodes the CD8α chain, which functions as a co-receptor for MHC class I: its immunoglobulin V-like extracellular domain binds the α3 domain of MHC-I (crystal structure resolved at 2.7 Å), its cytoplasmic tail associates with the Src-family kinase p56lck via a zinc clasp structure to phosphorylate CD3ζ and initiate TCR signaling, with CD8αβ heterodimers (but not CD8αα homodimers) achieving superior coreceptor function through CD8β palmitoylation/raft localization in mice or heterodimer-driven raft association in humans; additionally, CD8αα binds the non-classical MHC-I molecule TL to modulate intestinal T cell responses, soluble MHC-I molecules can ligate CD8α to induce FasL-mediated apoptosis, CEACAM5 activates Lck through CD8α binding, ADP-ribosylation of CD8β impairs coreceptor function, and CD8α maintains peripheral T cell quiescence through interaction with PILRα.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD8A encodes the CD8α chain, a key TCR co-receptor on cytotoxic T lymphocytes that both amplifies antigen-specific MHC class I signaling and maintains peripheral T cell quiescence through distinct ligand interactions. The CD8αα homodimer binds MHC class I molecules at the α2/α3 and β2-microglobulin interface in an antibody-antigen-like interaction [PMID:9177355], but full co-receptor function—including lipid raft partitioning, p56lck recruitment, CD3ζ phosphorylation, and cytotoxicity—requires assembly of the CD8αβ heterodimer, which is driven by extracellular domain interactions and CD8β palmitoylation [PMID:10925291, PMID:17341584, PMID:17506031]. CD8 co-receptor activity is negatively regulated by ADP-ribosylation of CD8β by ART2.2, which impairs MHC class I tetramer binding and suppresses cytotoxicity in vivo [PMID:23575529]. Independent of TCR signaling, CD8α engages PILRα on neighboring cells to enforce quiescence of naïve and memory CD8+ T cells in peripheral lymphoid organs; loss of this interaction causes spontaneous activation and death [PMID:35617401].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Determining how CD8α physically contacts MHC class I was unknown; the crystal structure of CD8αα–HLA-A2 revealed that CD8 clamps a flexible loop of the MHC α3 domain between CDR-like loops while also contacting β2-microglobulin, establishing the structural basis for co-receptor binding.\",\n      \"evidence\": \"X-ray crystallography of CD8αα–HLA-A2 complex at 2.7 Å resolution\",\n      \"pmids\": [\"9177355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure solved for CD8αα homodimer only; the CD8αβ heterodimer–MHC I interface remains unresolved\",\n        \"Binding affinity contributions of individual contact residues not dissected\",\n        \"How CD8 engagement couples to intracellular signaling was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"How CD8 engagement transduces intracellular signals was unclear; palmitoylation of CD8β was shown to drive CD8αβ (but not CD8αα) into lipid rafts, concentrating the co-receptor with p56lck and enabling CD3ζ phosphorylation—establishing the raft-dependent signaling mechanism of CD8.\",\n      \"evidence\": \"CD8 transfectants in T cell hybridomas with lipid raft fractionation, palmitoylation assays, cytoplasmic domain deletions, and p56lck activation readouts\",\n      \"pmids\": [\"10925291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of palmitoylation versus heterodimer assembly to raft partitioning not fully separated\",\n        \"Stoichiometry of CD8–Lck complex in rafts undefined\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether palmitoylation or heterodimer assembly was the primary determinant of raft localization was unresolved; chimeric constructs demonstrated that extracellular domain–mediated CD8αβ heterodimer formation, not palmitoylation alone, is the key requirement for raft partitioning and that CD8β is essential for co-receptor function of CD8-dependent TCRs.\",\n      \"evidence\": \"Chimeric CD8 constructs with raft fractionation in human T cells; retroviral TCR gene transfer into CD8β-deficient mouse T cells with cytotoxicity assays\",\n      \"pmids\": [\"17341584\", \"17506031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of how CD8αβ extracellular domains differ from CD8αα in enabling raft access is unknown\",\n        \"Whether CD8αα homodimers have any co-receptor function with low-avidity TCRs not excluded\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extrinsic regulatory mechanisms of CD8 co-receptor function were unknown; ADP-ribosylation of CD8β by ART2.2 was shown to impair MHC I tetramer binding and reduce cytotoxicity in vivo, identifying a post-translational switch that negatively regulates CD8 co-receptor activity.\",\n      \"evidence\": \"NAD+ treatment of T cells in vitro, ART2-deficient mice, MHC I tetramer binding, and in vivo cytotoxicity assays\",\n      \"pmids\": [\"23575529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific arginine residue(s) modified and their structural context on CD8β are not mapped\",\n        \"Physiological conditions controlling extracellular NAD+ availability near T cells are unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether CD8α has functions beyond antigen-dependent co-receptor signaling was unknown; inducible deletion of CD8α caused spontaneous activation and death of CD8+ T cells, and identification of PILRα as a CD8α ligand revealed a tonic, antigen-independent signal that maintains peripheral CD8+ T cell quiescence.\",\n      \"evidence\": \"Inducible CD8α-deletion mouse model, ligand binding screen identifying PILRα, disruption of PILRα–CD8α interaction, flow cytometry of activation markers in both mouse and human cells\",\n      \"pmids\": [\"35617401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream signaling pathway from PILRα–CD8α interaction that enforces quiescence is uncharacterized\",\n        \"Whether PILRα engagement requires CD8αα homodimer or CD8αβ heterodimer is not determined\",\n        \"Cell types expressing PILRα in lymphoid organs and spatial context of interaction not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CD8αβ heterodimer interaction with MHC class I and Lck, the downstream signaling pathway linking PILRα–CD8α engagement to quiescence maintenance, and how CEACAM5-mediated Lck activation drives CD8+ suppressor function remain mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure of CD8αβ heterodimer bound to MHC class I or Lck\",\n        \"Signaling intermediates between PILRα–CD8α and quiescence enforcement unknown\",\n        \"CEACAM5-induced CD8+ suppressor T cell biology replicated by only one group\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\n      \"CD8αβ heterodimer\",\n      \"CD8αα homodimer\",\n      \"TCR-CD8-pMHC I complex\"\n    ],\n    \"partners\": [\n      \"CD8B\",\n      \"LCK\",\n      \"PILRA\",\n      \"B2M\",\n      \"CEACAM5\",\n      \"ART2B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CD8A encodes the α chain of the CD8 co-receptor, a single-pass transmembrane glycoprotein with an immunoglobulin V-like extracellular domain that binds the α3 domain of MHC class I molecules to enhance TCR signaling on cytotoxic T lymphocytes [PMID:3871356, PMID:2784196, PMID:9177355]. Its cytoplasmic tail recruits the Src-family kinase p56Lck through a zinc-dependent clasp structure, enabling Lck-mediated phosphorylation of CD3ζ and TCR signal transduction; superior coreceptor function requires the CD8αβ heterodimer, which partitions into lipid rafts—via CD8β palmitoylation in mice or heterodimer-driven ectodomain assembly in humans—concentrating Lck away from the phosphatase CD45 [PMID:2470098, PMID:14500983, PMID:10925291, PMID:17341584]. Beyond classical coreceptor activity, the CD8αα homodimer binds the nonclassical MHC molecule TL to modulate intestinal intraepithelial lymphocyte responses, and CD8α engagement by soluble MHC-I or CEACAM5 can trigger FasL-mediated apoptosis or Lck activation leading to suppressor T cell function, respectively [PMID:11729321, PMID:10843658, PMID:24104458]. CD8α also maintains peripheral T cell quiescence through interaction with PILRα; inducible loss of CD8α causes spontaneous activation and death of naïve and memory CD8+ T cells independently of antigen [PMID:35617401].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing the molecular identity of the CD8 co-receptor: cloning and sequencing of CD8A revealed a transmembrane glycoprotein with an Ig V-like domain, defining the gene product that marks cytotoxic T lymphocytes.\",\n      \"evidence\": \"Gene transfer, subtractive hybridization, cDNA/genomic cloning, and sequencing in T cell lines\",\n      \"pmids\": [\"3871356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partner or signaling function yet identified\", \"Structure of the extracellular domain unknown\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Two foundational functions were established simultaneously: CD8α binds the α3 domain of MHC class I (with a single residue at position 245 governing binding) and associates with p56Lck to phosphorylate CD3 subunits, linking CD8 to both antigen recognition and TCR signaling.\",\n      \"evidence\": \"Site-directed mutagenesis of HLA alleles with cell-cell binding assays; co-immunoprecipitation and in vitro kinase assays in T cells\",\n      \"pmids\": [\"2784196\", \"2470098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD8–MHC interaction unresolved\", \"Mechanism of CD8α–Lck association unknown at atomic level\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Crystal structure of the CD8α extracellular domain revealed an Ig V-like fold that homodimerizes as an Fv-like unit, providing the first atomic framework for understanding its MHC-binding surface.\",\n      \"evidence\": \"X-ray crystallography at 2.6 Å of soluble CD8α expressed in CHO cells\",\n      \"pmids\": [\"1547508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of CD8αα in complex with MHC-I not yet available\", \"No structural information on the CD8α–Lck interface\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The co-crystal of CD8αα with HLA-A2/peptide at 2.7 Å resolved how CD8 engages MHC-I: the two CD8α subunits clamp a flexible loop of the α3 domain (residues 223–229) between their CDR-like loops, contacting both α2/α3 and β2m, with geometry that precludes binding a second MHC molecule.\",\n      \"evidence\": \"X-ray crystallography at 2.7 Å resolution\",\n      \"pmids\": [\"9177355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of CD8αβ heterodimer with MHC-I\", \"Functional difference between CD8αα and CD8αβ coreceptor activity unexplained structurally\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The functional superiority of CD8αβ over CD8αα was mechanistically explained: CD8β palmitoylation drives heterodimer partitioning into lipid rafts where Lck is concentrated and CD45 is excluded, enabling efficient CD3ζ phosphorylation—a compartmentalization mechanism absent in the homodimer.\",\n      \"evidence\": \"Lipid raft fractionation, co-immunoprecipitation, phosphorylation assays, and CD8β cytoplasmic domain deletion mutants in T cell hybridomas (murine system)\",\n      \"pmids\": [\"10925291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human CD8αβ uses the same palmitoylation-dependent mechanism was unresolved\", \"Role of the CD8β extracellular domain in raft targeting not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that CD8αα has a distinct ligand—the nonclassical MHC molecule TL—established a non-coreceptor function for the homodimer: CD8αα–TL binding on intestinal intraepithelial lymphocytes modulates TCR responses independently of classical MHC-I restriction.\",\n      \"evidence\": \"TL tetramer staining, binding assays, and functional T cell response assays\",\n      \"pmids\": [\"11729321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD8αα–TL recognition unknown at this point\", \"Downstream signaling consequences of TL engagement unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Three advances deepened the mechanistic picture: (i) the CD8α–Lck zinc clasp structure was solved by NMR, showing zinc-dependent co-folding of unstructured tails; (ii) ILTs were shown to compete with CD8 for MHC-I α3 binding with quantified affinities; (iii) soluble MHC-I ligation of CD8 was shown to upregulate FasL and induce apoptosis in both CD8+ T and NK cells.\",\n      \"evidence\": \"NMR solution structure of CD8α–Lck–Zn²⁺ complex; SPR-based competitive binding; apoptosis and FasL assays with blocking antibodies\",\n      \"pmids\": [\"14500983\", \"12853576\", \"12594841\", \"10843658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether zinc clasp formation is regulated in vivo unknown\", \"Physiological significance of soluble MHC–CD8 apoptotic signaling in immune regulation unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Species-specific mechanisms of CD8αβ raft targeting were delineated: in human T cells, heterodimer ectodomain assembly (not palmitoylation) drives raft localization, with CD8β cytoplasmic arginines contributing—contrasting the murine palmitoylation-dependent mechanism. Separately, genetic reconstitution confirmed that only CD8αβ (not CD8αα) provides coreceptor function for CD8-dependent TCRs.\",\n      \"evidence\": \"Chimeric CD8 protein analysis with lipid raft fractionation in human cells; retroviral TCR transfer into wild-type and CD8β-deficient primary mouse T cells\",\n      \"pmids\": [\"17341584\", \"17506031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why CD8αα ectodomains exclude raft partitioning unknown\", \"No structure of the human CD8αβ heterodimer\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two modulatory inputs onto the CD8 coreceptor axis were identified: CEACAM5 binds CD8α via its glycosylated N-domain to activate Lck and generate suppressor CD8+ T cells, while ART2.2-mediated ADP-ribosylation of CD8β impairs MHC-I tetramer binding and cytotoxicity in vivo.\",\n      \"evidence\": \"Co-immunoprecipitation with domain/glycosylation mutants, Lck kinase and T cell suppression assays (CEACAM5); NAD+ treatment, tetramer binding, and in vivo cytotoxicity in ART2-deficient mice (ADP-ribosylation)\",\n      \"pmids\": [\"24104458\", \"23575529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CEACAM5–CD8α interaction validated only in one laboratory\", \"Physiological relevance of ADP-ribosylation of CD8β to immune regulation in vivo needs broader confirmation\", \"Structural basis of CEACAM5–CD8α binding unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-coreceptor homeostatic role for CD8α was established: inducible CD8α deletion causes spontaneous activation and death of naïve and memory CD8+ T cells, and PILRα was identified as a CD8α ligand whose disruption phenocopies this loss of quiescence—defining CD8α as a tonic quiescence signal independent of TCR-MHC interaction.\",\n      \"evidence\": \"Inducible CD8α knockout mice, flow cytometry phenotyping, co-immunoprecipitation identifying PILRα, functional disruption in mouse and human systems\",\n      \"pmids\": [\"35617401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of CD8α–PILRα interaction not characterized\", \"Whether PILRα competes with MHC-I for CD8α binding unknown\", \"Relevance to human autoimmune or immunodeficiency phenotypes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of the CD8αβ heterodimer (no crystal or cryo-EM structure exists), how the CD8α–PILRα quiescence signal is transduced intracellularly, and whether the multiple non-coreceptor functions of CD8α (TL binding, CEACAM5 engagement, soluble MHC-induced apoptosis, PILRα-mediated quiescence) are integrated or context-exclusive.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of CD8αβ heterodimer\", \"Intracellular signaling downstream of CD8α–PILRα unknown\", \"Functional hierarchy among multiple CD8α ligands in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 7, 11]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 4, 7, 8, 13, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 11, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"CD8αβ heterodimer\",\n      \"CD8αα homodimer\",\n      \"CD8α–Lck zinc clasp complex\",\n      \"TCR–CD3–CD8 signaling complex\"\n    ],\n    \"partners\": [\n      \"LCK\",\n      \"B2M\",\n      \"CEACAM5\",\n      \"PILRA\",\n      \"CD247\",\n      \"LILRB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}