{"gene":"CD8A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2022,"finding":"CD8α interacts with PILRα (paired immunoglobulin-like type 2 receptor alpha) in both mice and humans to maintain CD8+ T cells in a physiologically quiescent state in peripheral lymphoid organs. Inducible deletion of CD8α caused both naïve and memory CD8+ T cells to spontaneously acquire activation phenotypes and subsequently die without antigen exposure; disruption of the CD8α-PILRα interaction was sufficient to break CD8+ T cell quiescence.","method":"Inducible CD8α deletion (conditional knockout), identification of PILRα as CD8α ligand, functional quiescence assay, adoptive transfer","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic deletion with defined cellular phenotype, ligand identification, and functional validation in both mice and humans in a single focused study","pmids":["35617401"],"is_preprint":false},{"year":2007,"finding":"CD8α/α homodimers fail to provide co-receptor function for a CD8-dependent TCR, whereas CD8α/β heterodimers are required. Gene transfer of a CD8-dependent TCR into CD8β-deficient T cells abolished antigen-specific cytotoxicity, while a CD8-independent TCR retained function, demonstrating that the CD8β chain specifically enables co-receptor activity for certain TCRs.","method":"Retroviral gene transfer of TCR into CD8β-deficient primary T cells; antibody blocking with anti-CD8α and anti-CD8β; cytotoxicity and IFN-γ production assays","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct reconstitution by gene transfer into knockout T cells with functional readouts (cytotoxicity, cytokine), multiple orthogonal methods (blocking antibodies + gene transfer)","pmids":["17506031"],"is_preprint":false},{"year":2013,"finding":"ART2.2 (adenosine diphosphate ribosyl transferase 2.2) ADP-ribosylates CD8-β on arginine residues of its extracellular domain in the presence of extracellular NAD+, in vitro and in vivo. ADP-ribosylation of CD8-β impaired binding of MHC-I tetramers to CD8+ T cells and reduced CD8+ T cell-mediated cytotoxicity in vivo, demonstrating that this post-translational modification negatively regulates CD8αβ co-receptor function.","method":"In vitro and in vivo ADP-ribosylation assay; anti-CD8β antibody binding assay; OVA:MHC-I tetramer binding; in vivo cytotoxicity assay; ART2-deficient T cells as negative controls; ART2.2-inhibitory single-domain antibodies","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo biochemical assay with genetic knockout controls, multiple orthogonal functional readouts (tetramer binding, cytotoxicity), single rigorous study","pmids":["23575529"],"is_preprint":false},{"year":2013,"finding":"CEACAM5 binds CD8α via its N-domain on intestinal epithelial cells; this interaction requires N-domain glycosylation, and removal of N-domain glycosylated residues reduces CD8α binding affinity. CEACAM5-mediated CD8α binding activates CD8-associated Lck kinase in CD8+ T cells, and CEACAM5-activated CD8+ T cells acquire suppressive function (inhibiting CD4+ T cell proliferation in vitro in the presence of IL-15 or IL-7).","method":"Co-immunoprecipitation; monoclonal antibody blocking (B9, L12); Lck phosphorylation assay; CD8α binding affinity assay with glycosylation mutants; in vitro CD4+ T cell suppression assay","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with mutagenesis (glycosylation removal), Lck activation readout, and functional suppression assay; single lab, multiple orthogonal methods","pmids":["24104458"],"is_preprint":false},{"year":2014,"finding":"Heritable downregulation of CD8 (CD8A locus) during type 2 polarization of murine CD8+ effector T cells is associated with CpG methylation of several regions of the Cd8a locus in vitro and in vivo. The methylation pattern is maintained long-term after adoptive transfer. Partial Cd8a demethylation occurs when CD8(low) effector cells are re-exposed to IFN-γ and re-express CD8 together with type 1 cytokine profile. Distinct Cd8a methylation signatures distinguish naïve, polarized, and repolarized cells from thymic developmental stages.","method":"Bisulfite sequencing of Cd8a locus CpG sites; adoptive transfer; in vitro type 1/2 polarization; IFN-γ re-stimulation; flow cytometry for CD8 surface expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct bisulfite sequencing of the Cd8a locus correlated with functional protein expression changes in vitro and in vivo with multiple conditions, single rigorous study with multiple orthogonal methods","pmids":["24675400"],"is_preprint":false},{"year":2022,"finding":"CD8α-specific deletion in T cells (CD8αCre-ALK5flox/flox mice) demonstrated that TGFβ signaling through ALK5 (TGFβ receptor I) suppresses CXCR3 expression on CD8+ T cells by increasing Smad2 binding to the CXCR3 promoter, thereby limiting CD8+ T cell trafficking into tumors. ALK5-deficient CD8+ T cells exhibited increased CXCR3 expression and enhanced migration towards CXCL10, and in vivo CXCR3 blockade partially abrogated the survival advantage conferred by CD8-specific ALK5 deletion.","method":"Cell type-conditional TGFβ receptor I (ALK5) knockout mice using CD8αCre; chromatin immunoprecipitation (Smad2 at CXCR3 promoter); CXCR3 expression by flow cytometry; migration assay towards CXCL10; in vivo CXCR3 blockade","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional knockout with CD8αCre driver, ChIP for Smad2 at CXCR3 promoter, functional migration assay, and in vivo rescue experiment with CXCR3 blockade; multiple orthogonal methods in single study","pmids":["32273499"],"is_preprint":false}],"current_model":"CD8A encodes the CD8α chain that functions as a co-receptor (as CD8α/β heterodimer, but not CD8α/α homodimer) for TCR-mediated MHC class I recognition; CD8α interacts with PILRα to maintain peripheral T cell quiescence in the absence of antigen; CD8α binding to CEACAM5 on intestinal epithelial cells activates Lck and confers suppressive function; ADP-ribosylation of the CD8β chain by ART2.2 inhibits co-receptor function; and epigenetic CpG methylation of the Cd8a locus reversibly regulates CD8 surface levels during effector T cell polarization."},"narrative":{"mechanistic_narrative":"CD8A encodes the CD8α chain, a T cell co-receptor whose function in MHC class I-restricted antigen recognition and downstream Lck signaling is governed by its dimerization state, its extracellular ligands, and post-translational and epigenetic regulation [PMID:17506031, PMID:24104458]. Co-receptor activity for CD8-dependent TCRs requires the CD8α/β heterodimer; CD8α/α homodimers are insufficient, as gene transfer of a CD8-dependent TCR into CD8β-deficient T cells abolishes antigen-specific cytotoxicity [PMID:17506031]. Beyond MHC-I, CD8α engages additional ligands with distinct functional consequences: interaction with PILRα maintains naïve and memory CD8+ T cells in a quiescent state, and loss of this engagement drives spontaneous activation and death without antigen [PMID:35617401], whereas binding to N-domain-glycosylated CEACAM5 on intestinal epithelium activates CD8-associated Lck and confers suppressive function on CD8+ T cells [PMID:24104458]. Co-receptor function is dampened by ART2.2-mediated ADP-ribosylation of the CD8β chain, which impairs MHC-I tetramer binding and cytotoxicity [PMID:23575529], while CpG methylation of the Cd8a locus reversibly controls surface CD8 levels during effector T cell polarization [PMID:24675400]. The CD8α-Cre lineage has also been used to show that T cell-intrinsic TGFβ/ALK5–Smad2 signaling represses CXCR3 to limit CD8+ T cell trafficking into tumors [PMID:32273499].","teleology":[{"year":2007,"claim":"Established that co-receptor function for CD8-dependent TCRs is a property of the CD8α/β heterodimer rather than CD8α/α homodimers, defining the structural requirement for productive MHC-I co-recognition.","evidence":"Retroviral TCR gene transfer into CD8β-deficient primary T cells with anti-CD8α/anti-CD8β blocking and cytotoxicity/IFN-γ readouts","pmids":["17506031"],"confidence":"High","gaps":["Does not resolve the structural basis by which the β chain enables co-receptor activity","Restricted to a defined CD8-dependent versus CD8-independent TCR pair"]},{"year":2013,"claim":"Showed that CD8αβ co-receptor function is negatively regulated post-translationally by ADP-ribosylation, revealing an extracellular metabolic checkpoint on cytotoxicity.","evidence":"In vitro/in vivo ART2.2 ADP-ribosylation assays on CD8β arginines with MHC-I tetramer binding, in vivo cytotoxicity, and ART2-deficient controls","pmids":["23575529"],"confidence":"High","gaps":["Physiological contexts where extracellular NAD+ reaches modifying concentrations not defined","Effect on TCR signaling kinetics beyond tetramer binding not detailed"]},{"year":2013,"claim":"Identified CEACAM5 as a glycosylation-dependent CD8α ligand on intestinal epithelium that triggers Lck activation and imprints a suppressive program, expanding CD8α's ligand repertoire beyond MHC-I.","evidence":"Co-IP, antibody blocking, CD8α binding affinity with glycosylation mutants, Lck phosphorylation, and in vitro CD4+ suppression assay","pmids":["24104458"],"confidence":"Medium","gaps":["Single-lab study without in vivo genetic validation","Whether suppressive function operates in vivo in the gut not established"]},{"year":2014,"claim":"Demonstrated that surface CD8 levels are reversibly set by CpG methylation of the Cd8a locus during effector polarization, establishing an epigenetic layer of co-receptor regulation.","evidence":"Bisulfite sequencing of Cd8a CpG sites with type 1/2 polarization, IFN-γ restimulation, adoptive transfer, and flow cytometry","pmids":["24675400"],"confidence":"High","gaps":["Methyltransferases/demethylases acting on the locus not identified","Functional consequence of CD8(low) state for TCR signaling not measured"]},{"year":2022,"claim":"Defined a ligand-driven quiescence function for CD8α, showing that CD8α-PILRα engagement actively restrains antigen-independent activation of naïve and memory CD8+ T cells.","evidence":"Inducible CD8α conditional knockout, PILRα ligand identification, quiescence assays, and adoptive transfer in mice and humans","pmids":["35617401"],"confidence":"High","gaps":["Signaling pathway from CD8α-PILRα that enforces quiescence not delineated","Relationship between quiescence role and classical co-receptor role unresolved"]},{"year":2022,"claim":"Used CD8α-Cre lineage targeting to show T cell-intrinsic TGFβ/ALK5–Smad2 signaling represses CXCR3 and limits CD8+ T cell tumor infiltration.","evidence":"CD8αCre-ALK5flox conditional knockout, Smad2 ChIP at the CXCR3 promoter, CXCL10 migration assays, and in vivo CXCR3 blockade","pmids":["32273499"],"confidence":"High","gaps":["Reports a CD8α-Cre-driven pathway rather than a direct CD8α molecular function","Whether CD8α protein itself participates in this signaling not addressed"]},{"year":null,"claim":"How CD8α integrates its competing ligand engagements (MHC-I, PILRα, CEACAM5) and regulatory modifications into a unified signaling decision remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model reconciling distinct ligand interfaces","Crosstalk between epigenetic, post-translational, and ligand-based regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3]}],"complexes":["CD8αβ co-receptor heterodimer"],"partners":["CD8B","PILRA","CEACAM5","LCK"],"other_free_text":[]}},"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":2293,"is_preprint":false},{"pmid":"19008445","id":"PMC_19008445","title":"Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19008445","citation_count":1726,"is_preprint":false},{"pmid":"30520029","id":"PMC_30520029","title":"CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30520029","citation_count":1334,"is_preprint":false},{"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":1282,"is_preprint":false},{"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":801,"is_preprint":false},{"pmid":"9927520","id":"PMC_9927520","title":"CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo.","date":"1999","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9927520","citation_count":707,"is_preprint":false},{"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":516,"is_preprint":false},{"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":505,"is_preprint":false},{"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":410,"is_preprint":false},{"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":388,"is_preprint":false},{"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":347,"is_preprint":false},{"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":246,"is_preprint":false},{"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":204,"is_preprint":false},{"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":192,"is_preprint":false},{"pmid":"32273499","id":"PMC_32273499","title":"TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32273499","citation_count":191,"is_preprint":false},{"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":174,"is_preprint":false},{"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":170,"is_preprint":false},{"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":162,"is_preprint":false},{"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":160,"is_preprint":false},{"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":135,"is_preprint":false},{"pmid":"30659054","id":"PMC_30659054","title":"PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/30659054","citation_count":134,"is_preprint":false},{"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":134,"is_preprint":false},{"pmid":"38744281","id":"PMC_38744281","title":"Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor.","date":"2024","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/38744281","citation_count":133,"is_preprint":false},{"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":133,"is_preprint":false},{"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":123,"is_preprint":false},{"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":116,"is_preprint":false},{"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":112,"is_preprint":false},{"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":111,"is_preprint":false},{"pmid":"15172445","id":"PMC_15172445","title":"CD8(+) T-cell immunity to cytomegalovirus.","date":"2004","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15172445","citation_count":109,"is_preprint":false},{"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":98,"is_preprint":false},{"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},{"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},{"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":86,"is_preprint":false},{"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},{"pmid":"22174854","id":"PMC_22174854","title":"Distinct and overlapping effector functions of expanded human CD4+, CD8α+ and CD4-CD8α- invariant natural killer T cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22174854","citation_count":85,"is_preprint":false},{"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":81,"is_preprint":false},{"pmid":"32036604","id":"PMC_32036604","title":"Cytotoxic CD8+ Lymphocytes in the Tumor Microenvironment.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32036604","citation_count":76,"is_preprint":false},{"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":76,"is_preprint":false},{"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},{"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},{"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":64,"is_preprint":false},{"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},{"pmid":"30863403","id":"PMC_30863403","title":"Harnessing CD8+ T Cells Under HIV Antiretroviral Therapy.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30863403","citation_count":58,"is_preprint":false},{"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},{"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":51,"is_preprint":false},{"pmid":"36050300","id":"PMC_36050300","title":"Heterogeneity and transcriptome changes of human CD8+ T cells across nine decades of life.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36050300","citation_count":51,"is_preprint":false},{"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":51,"is_preprint":false},{"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},{"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":49,"is_preprint":false},{"pmid":"31748421","id":"PMC_31748421","title":"CD8+ Tc2 cells: underappreciated contributors to severe asthma.","date":"2019","source":"European respiratory review : an official journal of the European Respiratory Society","url":"https://pubmed.ncbi.nlm.nih.gov/31748421","citation_count":45,"is_preprint":false},{"pmid":"12392852","id":"PMC_12392852","title":"Proliferative arrest and cell cycle regulation in CD8(+)CD28(-) versus CD8(+)CD28(+) T cells.","date":"2002","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12392852","citation_count":45,"is_preprint":false},{"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":45,"is_preprint":false},{"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":44,"is_preprint":false},{"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":43,"is_preprint":false},{"pmid":"38693002","id":"PMC_38693002","title":"Immunometabolism of CD8+ T cell differentiation in cancer.","date":"2024","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38693002","citation_count":41,"is_preprint":false},{"pmid":"36907685","id":"PMC_36907685","title":"Exhausted CD8+ T cells face a developmental fork in the road.","date":"2023","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36907685","citation_count":41,"is_preprint":false},{"pmid":"38394230","id":"PMC_38394230","title":"The gene regulatory basis of bystander activation in CD8+ T cells.","date":"2024","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38394230","citation_count":35,"is_preprint":false},{"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":33,"is_preprint":false},{"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},{"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":31,"is_preprint":false},{"pmid":"24675400","id":"PMC_24675400","title":"Epigenetic plasticity of Cd8a locus during CD8(+) T-cell development and effector differentiation and reprogramming.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24675400","citation_count":31,"is_preprint":false},{"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":29,"is_preprint":false},{"pmid":"34047386","id":"PMC_34047386","title":"TCF-1 maintains CD8+ T cell stemness in tumor microenvironment.","date":"2021","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/34047386","citation_count":29,"is_preprint":false},{"pmid":"36794587","id":"PMC_36794587","title":"CD8+ T Cells Promote Pathological Angiogenesis in Ocular Neovascular Disease.","date":"2023","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36794587","citation_count":29,"is_preprint":false},{"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":28,"is_preprint":false},{"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":28,"is_preprint":false},{"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},{"pmid":"34218330","id":"PMC_34218330","title":"CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance.","date":"2021","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/34218330","citation_count":28,"is_preprint":false},{"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},{"pmid":"32086762","id":"PMC_32086762","title":"Monitoring CD8a+ T Cell Responses to Radiotherapy and CTLA-4 Blockade Using [64Cu]NOTA-CD8a PET Imaging.","date":"2020","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32086762","citation_count":27,"is_preprint":false},{"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},{"pmid":"27748447","id":"PMC_27748447","title":"Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27748447","citation_count":25,"is_preprint":false},{"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":25,"is_preprint":false},{"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":24,"is_preprint":false},{"pmid":"31913398","id":"PMC_31913398","title":"A strong CD8+ T cell-stimulating supramolecular hydrogel.","date":"2020","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/31913398","citation_count":24,"is_preprint":false},{"pmid":"27897162","id":"PMC_27897162","title":"Batf3 selectively determines acquisition of CD8+ dendritic cell phenotype and function.","date":"2016","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27897162","citation_count":24,"is_preprint":false},{"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":24,"is_preprint":false},{"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":23,"is_preprint":false},{"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},{"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":23,"is_preprint":false},{"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":23,"is_preprint":false},{"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":23,"is_preprint":false},{"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},{"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":21,"is_preprint":false},{"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":21,"is_preprint":false},{"pmid":"38994031","id":"PMC_38994031","title":"CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38994031","citation_count":20,"is_preprint":false},{"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},{"pmid":"36911660","id":"PMC_36911660","title":"Canine peripheral blood TCRαβ T cell atlas: Identification of diverse subsets including CD8A+ MAIT-like cells by combined single-cell transcriptome and V(D)J repertoire analysis.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36911660","citation_count":20,"is_preprint":false},{"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":20,"is_preprint":false},{"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":19,"is_preprint":false},{"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},{"pmid":"36911807","id":"PMC_36911807","title":"Shaping Heterogeneity of Naive CD8+ T Cell Pools.","date":"2023","source":"Immune network","url":"https://pubmed.ncbi.nlm.nih.gov/36911807","citation_count":19,"is_preprint":false},{"pmid":"40816269","id":"PMC_40816269","title":"Succinate preserves CD8+ T cell fitness to augment antitumor immunity.","date":"2025","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/40816269","citation_count":18,"is_preprint":false},{"pmid":"36741397","id":"PMC_36741397","title":"CD8+ T-cell immunity orchestrated by iNKT cells.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36741397","citation_count":18,"is_preprint":false},{"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},{"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},{"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":18,"is_preprint":false},{"pmid":"23640800","id":"PMC_23640800","title":"CD8A gene polymorphisms predict severity factors in chronic rhinosinusitis.","date":"2013","source":"International forum of allergy & rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/23640800","citation_count":18,"is_preprint":false},{"pmid":"40579556","id":"PMC_40579556","title":"The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.","date":"2025","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40579556","citation_count":17,"is_preprint":false},{"pmid":"31494954","id":"PMC_31494954","title":"A molecular signature for CD8+ T cells from visceral leishmaniasis patients.","date":"2019","source":"Parasite immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31494954","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43252,"output_tokens":2118,"usd":0.080763,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9260,"output_tokens":2529,"usd":0.054762,"stage2_stop_reason":"end_turn"},"total_usd":0.135525,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CD8α interacts with PILRα (paired immunoglobulin-like type 2 receptor alpha) in both mice and humans to maintain CD8+ T cells in a physiologically quiescent state in peripheral lymphoid organs. Inducible deletion of CD8α caused both naïve and memory CD8+ T cells to spontaneously acquire activation phenotypes and subsequently die without antigen exposure; disruption of the CD8α-PILRα interaction was sufficient to break CD8+ T cell quiescence.\",\n      \"method\": \"Inducible CD8α deletion (conditional knockout), identification of PILRα as CD8α ligand, functional quiescence assay, adoptive transfer\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic deletion with defined cellular phenotype, ligand identification, and functional validation in both mice and humans in a single focused study\",\n      \"pmids\": [\"35617401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD8α/α homodimers fail to provide co-receptor function for a CD8-dependent TCR, whereas CD8α/β heterodimers are required. Gene transfer of a CD8-dependent TCR into CD8β-deficient T cells abolished antigen-specific cytotoxicity, while a CD8-independent TCR retained function, demonstrating that the CD8β chain specifically enables co-receptor activity for certain TCRs.\",\n      \"method\": \"Retroviral gene transfer of TCR into CD8β-deficient primary T cells; antibody blocking with anti-CD8α and anti-CD8β; cytotoxicity and IFN-γ production assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct reconstitution by gene transfer into knockout T cells with functional readouts (cytotoxicity, cytokine), multiple orthogonal methods (blocking antibodies + gene transfer)\",\n      \"pmids\": [\"17506031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ART2.2 (adenosine diphosphate ribosyl transferase 2.2) ADP-ribosylates CD8-β on arginine residues of its extracellular domain in the presence of extracellular NAD+, in vitro and in vivo. ADP-ribosylation of CD8-β impaired binding of MHC-I tetramers to CD8+ T cells and reduced CD8+ T cell-mediated cytotoxicity in vivo, demonstrating that this post-translational modification negatively regulates CD8αβ co-receptor function.\",\n      \"method\": \"In vitro and in vivo ADP-ribosylation assay; anti-CD8β antibody binding assay; OVA:MHC-I tetramer binding; in vivo cytotoxicity assay; ART2-deficient T cells as negative controls; ART2.2-inhibitory single-domain antibodies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo biochemical assay with genetic knockout controls, multiple orthogonal functional readouts (tetramer binding, cytotoxicity), single rigorous study\",\n      \"pmids\": [\"23575529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM5 binds CD8α via its N-domain on intestinal epithelial cells; this interaction requires N-domain glycosylation, and removal of N-domain glycosylated residues reduces CD8α binding affinity. CEACAM5-mediated CD8α binding activates CD8-associated Lck kinase in CD8+ T cells, and CEACAM5-activated CD8+ T cells acquire suppressive function (inhibiting CD4+ T cell proliferation in vitro in the presence of IL-15 or IL-7).\",\n      \"method\": \"Co-immunoprecipitation; monoclonal antibody blocking (B9, L12); Lck phosphorylation assay; CD8α binding affinity assay with glycosylation mutants; in vitro CD4+ T cell suppression assay\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with mutagenesis (glycosylation removal), Lck activation readout, and functional suppression assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24104458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Heritable downregulation of CD8 (CD8A locus) during type 2 polarization of murine CD8+ effector T cells is associated with CpG methylation of several regions of the Cd8a locus in vitro and in vivo. The methylation pattern is maintained long-term after adoptive transfer. Partial Cd8a demethylation occurs when CD8(low) effector cells are re-exposed to IFN-γ and re-express CD8 together with type 1 cytokine profile. Distinct Cd8a methylation signatures distinguish naïve, polarized, and repolarized cells from thymic developmental stages.\",\n      \"method\": \"Bisulfite sequencing of Cd8a locus CpG sites; adoptive transfer; in vitro type 1/2 polarization; IFN-γ re-stimulation; flow cytometry for CD8 surface expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct bisulfite sequencing of the Cd8a locus correlated with functional protein expression changes in vitro and in vivo with multiple conditions, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"24675400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD8α-specific deletion in T cells (CD8αCre-ALK5flox/flox mice) demonstrated that TGFβ signaling through ALK5 (TGFβ receptor I) suppresses CXCR3 expression on CD8+ T cells by increasing Smad2 binding to the CXCR3 promoter, thereby limiting CD8+ T cell trafficking into tumors. ALK5-deficient CD8+ T cells exhibited increased CXCR3 expression and enhanced migration towards CXCL10, and in vivo CXCR3 blockade partially abrogated the survival advantage conferred by CD8-specific ALK5 deletion.\",\n      \"method\": \"Cell type-conditional TGFβ receptor I (ALK5) knockout mice using CD8αCre; chromatin immunoprecipitation (Smad2 at CXCR3 promoter); CXCR3 expression by flow cytometry; migration assay towards CXCL10; in vivo CXCR3 blockade\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional knockout with CD8αCre driver, ChIP for Smad2 at CXCR3 promoter, functional migration assay, and in vivo rescue experiment with CXCR3 blockade; multiple orthogonal methods in single study\",\n      \"pmids\": [\"32273499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD8A encodes the CD8α chain that functions as a co-receptor (as CD8α/β heterodimer, but not CD8α/α homodimer) for TCR-mediated MHC class I recognition; CD8α interacts with PILRα to maintain peripheral T cell quiescence in the absence of antigen; CD8α binding to CEACAM5 on intestinal epithelial cells activates Lck and confers suppressive function; ADP-ribosylation of the CD8β chain by ART2.2 inhibits co-receptor function; and epigenetic CpG methylation of the Cd8a locus reversibly regulates CD8 surface levels during effector T cell polarization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD8A encodes the CD8α chain, a T cell co-receptor whose function in MHC class I-restricted antigen recognition and downstream Lck signaling is governed by its dimerization state, its extracellular ligands, and post-translational and epigenetic regulation [#1, #3]. Co-receptor activity for CD8-dependent TCRs requires the CD8α/β heterodimer; CD8α/α homodimers are insufficient, as gene transfer of a CD8-dependent TCR into CD8β-deficient T cells abolishes antigen-specific cytotoxicity [#1]. Beyond MHC-I, CD8α engages additional ligands with distinct functional consequences: interaction with PILRα maintains naïve and memory CD8+ T cells in a quiescent state, and loss of this engagement drives spontaneous activation and death without antigen [#0], whereas binding to N-domain-glycosylated CEACAM5 on intestinal epithelium activates CD8-associated Lck and confers suppressive function on CD8+ T cells [#3]. Co-receptor function is dampened by ART2.2-mediated ADP-ribosylation of the CD8β chain, which impairs MHC-I tetramer binding and cytotoxicity [#2], while CpG methylation of the Cd8a locus reversibly controls surface CD8 levels during effector T cell polarization [#4]. The CD8α-Cre lineage has also been used to show that T cell-intrinsic TGFβ/ALK5–Smad2 signaling represses CXCR3 to limit CD8+ T cell trafficking into tumors [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that co-receptor function for CD8-dependent TCRs is a property of the CD8α/β heterodimer rather than CD8α/α homodimers, defining the structural requirement for productive MHC-I co-recognition.\",\n      \"evidence\": \"Retroviral TCR gene transfer into CD8β-deficient primary T cells with anti-CD8α/anti-CD8β blocking and cytotoxicity/IFN-γ readouts\",\n      \"pmids\": [\"17506031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the structural basis by which the β chain enables co-receptor activity\", \"Restricted to a defined CD8-dependent versus CD8-independent TCR pair\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that CD8αβ co-receptor function is negatively regulated post-translationally by ADP-ribosylation, revealing an extracellular metabolic checkpoint on cytotoxicity.\",\n      \"evidence\": \"In vitro/in vivo ART2.2 ADP-ribosylation assays on CD8β arginines with MHC-I tetramer binding, in vivo cytotoxicity, and ART2-deficient controls\",\n      \"pmids\": [\"23575529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where extracellular NAD+ reaches modifying concentrations not defined\", \"Effect on TCR signaling kinetics beyond tetramer binding not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CEACAM5 as a glycosylation-dependent CD8α ligand on intestinal epithelium that triggers Lck activation and imprints a suppressive program, expanding CD8α's ligand repertoire beyond MHC-I.\",\n      \"evidence\": \"Co-IP, antibody blocking, CD8α binding affinity with glycosylation mutants, Lck phosphorylation, and in vitro CD4+ suppression assay\",\n      \"pmids\": [\"24104458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without in vivo genetic validation\", \"Whether suppressive function operates in vivo in the gut not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that surface CD8 levels are reversibly set by CpG methylation of the Cd8a locus during effector polarization, establishing an epigenetic layer of co-receptor regulation.\",\n      \"evidence\": \"Bisulfite sequencing of Cd8a CpG sites with type 1/2 polarization, IFN-γ restimulation, adoptive transfer, and flow cytometry\",\n      \"pmids\": [\"24675400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferases/demethylases acting on the locus not identified\", \"Functional consequence of CD8(low) state for TCR signaling not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a ligand-driven quiescence function for CD8α, showing that CD8α-PILRα engagement actively restrains antigen-independent activation of naïve and memory CD8+ T cells.\",\n      \"evidence\": \"Inducible CD8α conditional knockout, PILRα ligand identification, quiescence assays, and adoptive transfer in mice and humans\",\n      \"pmids\": [\"35617401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from CD8α-PILRα that enforces quiescence not delineated\", \"Relationship between quiescence role and classical co-receptor role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used CD8α-Cre lineage targeting to show T cell-intrinsic TGFβ/ALK5–Smad2 signaling represses CXCR3 and limits CD8+ T cell tumor infiltration.\",\n      \"evidence\": \"CD8αCre-ALK5flox conditional knockout, Smad2 ChIP at the CXCR3 promoter, CXCL10 migration assays, and in vivo CXCR3 blockade\",\n      \"pmids\": [\"32273499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reports a CD8α-Cre-driven pathway rather than a direct CD8α molecular function\", \"Whether CD8α protein itself participates in this signaling not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD8α integrates its competing ligand engagements (MHC-I, PILRα, CEACAM5) and regulatory modifications into a unified signaling decision remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model reconciling distinct ligand interfaces\", \"Crosstalk between epigenetic, post-translational, and ligand-based regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [\"CD8\\u03b1\\u03b2 co-receptor heterodimer\"],\n    \"partners\": [\"CD8B\", \"PILRA\", \"CEACAM5\", \"LCK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}