{"gene":"CD1C","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1987,"finding":"CD1c (along with CD1a and CD1b) was identified as a member of a family of antigen-presenting molecules distantly related to MHC class I, with a beta2-microglobulin-binding domain and characteristic intron-exon structure. CD1c has a duplicated form of a conserved 5'-untranslated exon. The genes were identified by transfection into mouse cells, which then expressed the surface antigens recognized by cluster-defining monoclonal antibodies.","method":"Gene transfection into mouse cells, genomic DNA sequencing, cDNA cloning, monoclonal antibody recognition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct gene identification, expression in transfectants, structural analysis with mutagenesis-level domain mapping; foundational paper","pmids":["2447586"],"is_preprint":false},{"year":1988,"finding":"CD1c expression is restricted to a subset of B cells (mantle zone B cells in lymphoid organs and ~50% of peripheral blood/spleen B cells), whereas CD1a and CD1b are not expressed on B or T cells. CD1c expression is upregulated on B cells upon BCR activation and induced de novo on previously CD1c-negative B cells in vitro, while activated T cells remain CD1c-negative.","method":"Flow cytometry, in vitro B cell activation, immunofluorescence, ultrastructural analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (flow cytometry, ultrastructure, in vitro activation), replicated pattern across tissues","pmids":["3260523"],"is_preprint":false},{"year":1990,"finding":"CD1c molecules on target cell surfaces can serve as recognition structures for a subset of gamma/delta T cells. Only rare peripheral blood gamma/delta clones (using Vdelta1/J1 rearrangement) interact with targets via a CD1c-dependent recognition pathway, indicating CD1c does not have a broad contribution to the peripheral gamma/delta T cell repertoire.","method":"Cytotoxicity assays using 43 cloned and 11 polyclonal gamma/delta T cell lines; blocking with anti-CD1c antibody","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with antibody in multiple cell lines, single lab","pmids":["1690662"],"is_preprint":false},{"year":1996,"finding":"CD1c functions as an antigen-presenting molecule that restricts mycobacteria-specific T cell responses. CD1c-restricted T cell lines recognize protease-resistant mycobacterial lipid antigens in an MHC-unrestricted, TAP-1/2- and DMA/B-independent manner. A subpopulation of T cells also shows direct cytotoxicity toward CD1c-expressing target cells without mycobacterial antigen, indicating autoreactivity to CD1c itself.","method":"T cell line derivation from donor blood, cytotoxicity assays, MHC-blocking, TAP/DM independence testing, clonal analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, cytokine, blocking), replicated across clones and donors","pmids":["8816382"],"is_preprint":false},{"year":2000,"finding":"CD1c presents an evolutionarily conserved family of isoprenoid glycolipids including mycobacterial hexosyl-1-phosphoisoprenoids and mannosyl-beta1-phosphodolichols. T cell recognition via CD1c and the T cell antigen receptor was demonstrated for these lipid antigens, with T cell responses observed in M. tuberculosis-infected subjects but not naive controls.","method":"CD1c-restricted T cell line recognition assays, mass spectrometry-based lipid identification, ex vivo T cell responses from infected vs. naive subjects","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical identification of antigens combined with functional T cell assays and clinical validation","pmids":["10786796"],"is_preprint":false},{"year":2000,"finding":"CD1c distributes predominantly at the cell surface with minimal intracellular accumulation in human dendritic cells, contrasting with CD1b which accumulates in lysosomal MHC class II compartments. Intracellular CD1c localizes to early and late endosomes, not lysosomes. Deletion of the cytoplasmic tail tyrosine-based internalization motif of CD1c abolishes most intracellular localization. CD1c-mediated antigen presentation is resistant to endosomal acidification inhibitors and is independent of endosomal localization, distinguishing it mechanistically from CD1b.","method":"Subcellular fractionation, confocal microscopy, tail-deletion mutagenesis, pharmacological inhibition of endosomal acidification, T cell functional assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct localization experiments with mutagenesis and functional validation in same study","pmids":["10899914"],"is_preprint":false},{"year":2000,"finding":"CD1c-restricted double-negative (DN) T cells from SLE patients provide help to CD1c+ B cells for IgG production and isotype switching. Anti-CD1c blocking antibodies inhibit DN T cell-induced IgG production, and anti-IL-4 neutralization also inhibits IgG production, correlating with IL-4 production by DN T cells from SLE patients. DN T cells from healthy donors induced only IgM with CD1c+ B cells.","method":"T cell-B cell co-culture, antibody blocking (anti-CD1c, anti-IL-4), cytokine measurement (IL-4, IFN-gamma)","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal blocking experiments and cytokine measurement, single lab","pmids":["11046069"],"is_preprint":false},{"year":2000,"finding":"GPI-reanchored CD1c (CD1c.DAF) maintains the ability to present mycobacterial antigens to CD1c-restricted T cells as efficiently as native CD1c, whereas GPI-reanchored CD1b is less efficient than native CD1b. This demonstrates that CD1c and CD1b have distinct, non-overlapping antigen-presenting pathways, with CD1c accessing antigen-loading compartments that do not require the cytoplasmic tail-directed trafficking used by CD1b.","method":"GPI-reanchored fusion protein engineering, cytotoxicity and cytokine release assays with CD1c-restricted and CD1b-restricted T cell lines, PI-PLC treatment to confirm GPI anchoring","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — engineered GPI variants with functional reconstitution and direct comparison between isoforms","pmids":["10903726"],"is_preprint":false},{"year":2004,"finding":"The M. tuberculosis gene pks12 encodes a polyketide synthase responsible for producing CD1c-presented mycoketide antigens (C30-34 branched alkane lipids). Genetic deletion and complementation of pks12 demonstrated it is necessary for antigen production. The lipid moiety distinguishes mycobacterial antigens from mammalian mannosyl-beta1-phosphodolichols and is required for activation of CD1c-restricted T cells.","method":"Metabolic radiolabeling, mass spectrometry, genetic deletion and complementation of pks12 in M. tuberculosis, T cell activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic epistasis (deletion/complementation) combined with biochemical characterization and functional T cell assays","pmids":["15611286"],"is_preprint":false},{"year":2005,"finding":"CD1c-restricted, glycolipid-specific T cells accumulate in inflamed thyroid tissue during Graves' disease and Hashimoto's thyroiditis but were not detected in peripheral blood. Polyclonal thyroid-derived lymphocytes and T cell lines lyse targets in a CD1c-dependent manner. CD1c is expressed on CD83+ dendritic cells and on CD20+ IgD+ mantle zone B cells within thyroid lymphoid follicles.","method":"Immunofluorescence of thyroid tissue, ex vivo T cell line derivation, cytotoxicity assays with CD1c-blocking antibodies","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays with CD1c blocking, tissue localization, single lab","pmids":["15749918"],"is_preprint":false},{"year":2007,"finding":"CD1c presentation of synthetic mannosyl phosphomycoketide antigens requires both a phosphate group and a beta-linked mannose unit. T cell responses show preference for C30-34 lipid units with methyl branches in the S-configuration, matching the stereospecific output of mycobacterial pks12. Stereorandom branching is insufficient for T cell activation, indicating that CD1c-restricted T cells detect a bacterial-specific polyketide lipid pattern.","method":"Synthetic chemistry (stereorandom and stereospecific analogs), T cell activation assays with CD1c-restricted T cell lines","journal":"Chemistry & biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic structure-activity relationship using synthetic analogs with defined stereochemistry, functional T cell readout","pmids":["18022562"],"is_preprint":false},{"year":2009,"finding":"CD1c can present a lipopeptide antigen (N-acyl glycine dodecamer, lipo-12) to human T cells in a manner dependent on the acyl linkage, peptide length, and sequence. Unlike CD1b-presented antigens that require lysosomal processing, rerouting CD1c to lysosomes by mutating its cytoplasmic tail sequences reduces lipo-12 presentation. This demonstrates that CD1c surveys early endosomal/non-lysosomal pathways and that certain antigens are destroyed in lysosomes.","method":"Synthetic lipopeptide T cell activation assays, CD1c tail mutation to redirect trafficking, protease inhibitor treatment, CD1c transfection","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of CD1c tail, pharmacological manipulation, reconstitution with synthetic antigen, multiple mechanistic controls","pmids":["19468063"],"is_preprint":false},{"year":2011,"finding":"Mass spectrometry analysis of highly purified CD1c protein identified 11 novel self-lipids specifically loaded into CD1c's lipid-binding site, including lipids distinct from those presented by CD1d. The distinct but overlapping lipid populations identified for each CD1 family member imply that CD1c surveys specific endoplasmic reticulum, Golgi, and/or secretory compartments in addition to endocytic compartments.","method":"Affinity purification of CD1c protein, mass spectrometry with rigorous controls for specificity of lipid binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry with purified protein and rigorous controls establishing specific lipid binding","pmids":["21900247"],"is_preprint":false},{"year":2011,"finding":"CD1c expression and function in human B cells are regulated by activation signals. BCR activation significantly upregulates CD1c expression particularly on marginal zone-like B cells, while CD40L stimulation downregulates CD1c. The CD40L-induced downregulation of CD1c correlates with diminished retinoic acid receptor alpha (RARα) response gene expression, which is reversed by RARα agonists. BCR-induced CD1c upregulation is RAR-independent.","method":"In vitro B cell activation, flow cytometry, RARα agonist treatment, gene expression analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple activation conditions and pharmacological pathway dissection, single lab","pmids":["21451111"],"is_preprint":false},{"year":2012,"finding":"CD1c can interact specifically with immunoglobulin-like transcript 4 (ILT4) with higher affinity than CD1d. Upregulation of CD1c expression enhances NKT cell recognition of CD1d, while downregulation reduces CD1d recognition. The proposed mechanism is that CD1c acts as a sink for the inhibitory receptor ILT4, reducing ILT4-mediated inhibition of CD1d.","method":"Binding affinity measurements, CD1c overexpression and knockdown, NKT cell co-culture functional assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding data combined with gain/loss-of-function experiments, single lab","pmids":["22888216"],"is_preprint":false},{"year":2012,"finding":"In rhesus macaques vaccinated with BCG, the major T cell response to glucose monomycolate (GMM), a mycolate-containing glycolipid normally thought to be CD1b-restricted in humans, is restricted by CD1c rather than CD1b. GMM-specific CD1c-restricted T cells produced IFN-γ and TNF-α, and could extravasate to sites of infection where CD1c+ cells accumulated.","method":"BCG vaccination of macaques, T cell proliferation assays with CD1b/CD1c blocking antibodies, cytokine analysis, immunohistochemistry of infection sites","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with antibody blocking and functional characterization, single lab","pmids":["23132493"],"is_preprint":false},{"year":2013,"finding":"CD1c-restricted T cells recognize C32 phosphomycoketide (PM) as a CD1c-presented antigen, with antigen binding and presentation requiring the unusual mycobacteria-specific methyl-branched lipid pattern from pks12. Antigen processing by dendritic cells and B cells generates a deglycosylated phosphomycoketide neoepitope — cell-free systems showed recognition only of the deglycosylated form. CD1c tetramers loaded with PM stain T cell receptors directly, providing biophysical evidence for a ternary CD1c-lipid-TCR interaction, and detected polyclonal T cell responses ex vivo in human peripheral blood.","method":"CD1c tetramer staining, cell-free antigen presentation systems, T cell activation assays, ex vivo human blood T cell detection","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with tetramers, cell-free systems showing processing, direct TCR binding, and ex vivo validation","pmids":["23530121"],"is_preprint":false},{"year":2013,"finding":"Human CD1c+ myeloid DCs (mDC1) are the only human DC subset to secrete high amounts of IL-12p70 (requiring combinational TLR stimulation), and they are fully equipped to cross-prime naive CD8+ T cells, inducing the highest levels of cytotoxic molecules due to IL-12 production. CD1c+ DCs required different TLR ligand combinations for cross-presentation compared to BDCA-3+ DCs.","method":"Purification of blood DC subsets, TLR stimulation, intracellular cytokine staining, naive CD8+ T cell priming assays, cross-presentation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays across DC subsets, replicated comparisons","pmids":["23794066"],"is_preprint":false},{"year":2013,"finding":"CD1c+ blood myeloid DCs respond to E. coli with an immunoregulatory rather than inflammatory phenotype: they produce high IL-10 and regulatory molecules IDO and soluble CD25, but only low TNF, IL-6, and IL-12. E. coli-activated CD1c+ DCs suppress T cell proliferation in an IL-10-dependent manner, distinguishing them functionally from monocyte-derived DCs.","method":"Purified blood DC stimulation with E. coli, multiplex cytokine measurement, T cell suppression assays with IL-10 neutralization","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cytokine endpoints with mechanistic neutralization, single lab","pmids":["22678905"],"is_preprint":false},{"year":2013,"finding":"Lung-tissue-resident CD1c+ DCs, but not CD141+ DCs, drive CD103 expression on CD8+ T cells and promote CD8+ T cell accumulation in lung epithelia. CD1c+ DC induction of CD103 expression is dependent on membrane-bound TGF-β1.","method":"Human lung tissue DC isolation, humanized mouse model, in vitro and in vivo CD8+ T cell priming assays, TGF-β1 blocking/neutralization","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo experiments with cytokine-blocking mechanistic validation, both human tissue and humanized mouse model","pmids":["23562160"],"is_preprint":false},{"year":2013,"finding":"CD1c+ blood myeloid DCs stimulate a strong IL-12-independent IFN-γ (Th1) response, in contrast to monocyte-derived DCs which induce IL-12-dependent Th1 responses. This was validated in a patient with severely impaired IL-12 production, whose CD1c+ DCs induced normal Th1 responses while his moDC failed. CD1c+ DCs showed minimal upregulation of inflammatory-associated genes compared to moDC.","method":"IL-12 neutralization in co-culture assays, patient with IL-12 deficiency as natural experiment, microarray gene expression analysis","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway dissection with neutralizing antibody plus natural genetic experiment (IL-12-deficient patient), corroborated by transcriptomics","pmids":["25765676"],"is_preprint":false},{"year":2013,"finding":"CD1c+ myeloid DCs acquire high retinoic acid-producing capacity (RALDH2 expression and ALDH activity) in response to vitamin D3 in the presence of GM-CSF, via a p38-dependent pathway. RALDH2-high CD1c+ DCs stimulate naive CD4+ T cells to express gut-homing molecules and produce Th2 cytokines in an RA-dependent manner. TLR ligands or TNF abrogate this ALDH activity.","method":"RALDH2 mRNA quantification, ALDH activity assays, vitamin D3 stimulation, p38 inhibition, T cell gut-homing assays with RA blockade","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay with pharmacological inhibitors and functional T cell readout, single lab","pmids":["23966631"],"is_preprint":false},{"year":2014,"finding":"CD1c presents a novel class of self-lipids—methyl-lysophosphatidic acids (mLPAs)—that accumulate in leukemia cells. mLPA-specific CD1c-restricted T cells efficiently kill CD1c+ acute leukemia cells in vitro and protect immunodeficient mice against CD1c+ human leukemia cells in vivo.","method":"Lipid biochemistry to identify mLPA, T cell recognition assays with CD1c-blocking, in vitro cytotoxicity, xenograft mouse model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel antigen identification plus in vitro and in vivo functional validation with blocking controls","pmids":["24935257"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of CD1c with phosphomycoketide (PM) shows the A' pocket accommodates the mycoketide alkyl chain, with the phosphate head-group shifted ~6 Å compared to mannosyl-β1-PM. Six human TCRs show high-to-moderate affinity interactions with CD1c-mycoketide complexes. Mutagenesis of CD1c reveals residues in both α1 and α2 helices involved in TCR recognition, with no single archetypical binding footprint shared among CD1c-reactive TCRs.","method":"X-ray crystallography of CD1c-PM complex, surface plasmon resonance (TCR binding affinity), site-directed mutagenesis of CD1c residues, TCR CDR mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and direct binding measurements across multiple TCRs","pmids":["25298532"],"is_preprint":false},{"year":2014,"finding":"Langerin expression is rapidly induced on CD1c+ DCs by serum or TGF-β via an ALK-3-dependent pathway when DCs are isolated from blood and cultured. Langerin is not expressed on freshly isolated CD1c+ blood DCs but appears on CD1c+ DCs in tissues, indicating tissue microenvironment drives this phenotypic differentiation.","method":"Flow cytometry of tissue and blood DC subsets, TGF-β stimulation, ALK-3 inhibition, stem cell transplantation models","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with ALK-3 inhibitor and in vitro induction assay, single lab","pmids":["25516751"],"is_preprint":false},{"year":2014,"finding":"CD1c+ DCs can differentiate into Langerhans cell-like cells with high langerin expression, Birbeck granules, EpCAM, and E-cadherin when cultured with GM-CSF, TGF-β, and BMP7, making them far more LC-like than monocytes under the same conditions.","method":"In vitro differentiation assay with defined cytokine combinations, flow cytometry, electron microscopy for Birbeck granules","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined culture system with multiple readouts including ultrastructure, single lab","pmids":["25352125"],"is_preprint":false},{"year":2016,"finding":"CD1c tetramers loaded with phosphomycoketide bind Vδ1+ γδ TCRs with biophysical evidence for a direct CD1c–γδ TCR interaction. Mutational analysis demonstrates a role of the Vδ1 domain during recognition. CD1c-reactive γδ TCRs also bind CD1c complexes with diverse lipids (lysophosphatidylcholine, sulfatide, mannosyl-phosphomycoketide) but not lipopeptide ligands, revealing permissive and non-permissive lipid determinants.","method":"CD1c tetramer staining with Vδ subtype selection, TCR binding assays, Vδ1 domain mutagenesis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biophysical tetramer binding with mutagenesis identifying domain requirements, multiple lipid ligands tested","pmids":["26755823"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of CD1c at 2.4 Å reveals an extended ligand binding groove and a substantially different conformation from previously known CD1c structures. Computational simulations predict cholesteryl esters (CE) and acylated steryl glycosides (ASG) as CD1c ligands. Binding of CE and ASG to CD1c enables binding of human CD1c self-reactive T cell receptors, demonstrating that lipid occupancy stabilizes specific CD1c conformations that provide a footprint for autoreactive TCR binding.","method":"X-ray crystallography (2.4 Å), molecular dynamics simulations, lipid-loading assays, T cell receptor binding experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus molecular dynamics plus functional TCR binding validation in same study","pmids":["26884207"],"is_preprint":false},{"year":2018,"finding":"Human T cells frequently stain with CD1c tetramers carrying diverse self lipids, with TCRs showing extreme polyspecificity — autoreactivity occurs with CD1c loaded with numerous, chemically diverse self lipids. Crystal structure shows the TCR binds over the closed portal surface of CD1c where lipids normally protrude, with the TCR failing to contact lipids because they are fully sequestered within CD1c. Small lipid size is identified as a determinant of autoreactive T cell responses.","method":"CD1c tetramer staining with diverse lipids, X-ray crystallography of TCR-CD1c complex, mutational analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of TCR-CD1c complex directly reveals the sequestration mechanism, validated across multiple TCRs and lipids","pmids":["29531339"],"is_preprint":false},{"year":2016,"finding":"MiR-381-3p binds the 3'-UTR of the CD1c gene and suppresses CD1c mRNA expression in M. tuberculosis-infected dendritic cells. Inhibition of miR-381-3p in BCG-infected DCs reverses suppression of CD1c expression and promotes T cell responses against BCG. IL-10 upregulates miR-381-3p as part of an immunosuppressive circuit.","method":"Luciferase 3'-UTR reporter assay (bioinformatic prediction + validation), miR-381-3p inhibitor in BCG-infected DCs, T cell co-culture assays, in vivo miR-381-3p expression in TB patient DCs","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay for 3'-UTR targeting plus gain/loss-of-function in primary cells with functional T cell readout, single lab","pmids":["27296666"],"is_preprint":false},{"year":2003,"finding":"iC3b inhibits differentiation of CD11b+ monocytes into CD1c-expressing dendritic cell precursors. This inhibition is mediated through CD11b (the iC3b receptor) as an anti-CD11b blocking antibody reverses the effect. iC3b also inhibits IL-12p70 production and CD80/CD40 expression, causing a temporary arrest of DC differentiation.","method":"GM-CSF-induced monocyte differentiation in vitro, iC3b treatment, anti-CD11b blocking antibody, keratome biopsy-derived dermal cell analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro differentiation assay with receptor blocking antibody identifying mechanistic pathway, single lab","pmids":["12713585"],"is_preprint":false},{"year":2021,"finding":"Crystallographic studies of CD1c complexes with three hydrolysis-resistant MPM analogs (including difluoromethylene-modified MPM-3) show anchoring of the lipid tail and phosphate group highly comparable to native MPM, but with considerable conformational flexibility for the mannose head group. MPM-3, resistant to hydrolysis, shows altered recognition by T cells but not by CD1c proteins, supporting the cellular antigen processing hypothesis that glycolipid hydrolysis occurs during presentation.","method":"Synthetic chemistry, X-ray crystallography of CD1c-analog complexes, T cell activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of multiple CD1c-ligand complexes combined with functional T cell assays supporting processing mechanism","pmids":["34536421"],"is_preprint":false},{"year":2017,"finding":"Human CD1c+ DCs produce IL-12p70, IL-1β, IL-6, and IL-23 in response to combined TLR stimulation and are capable of promoting both Th1 (IFN-γ) and Th17 (IL-17A, IL-17F, IL-21, IL-22) effector function in memory CD4+ T cells.","method":"Purified blood CD1c+ DC TLR stimulation (R848+LPS or poly I:C), multiplex cytokine measurement, memory CD4+ T cell co-culture with cytokine readout","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — purified primary cell functional assays with defined TLR stimuli, single lab","pmids":["28878767"],"is_preprint":false},{"year":2018,"finding":"CLEC10A (CD301) is identified as a specific endocytic receptor on human CD1c+ DCs. CLEC10A rapidly internalizes upon monoclonal antibody binding. A bivalent CLEC10A-specific ligand (MUC-1 peptide glycosylated with N-acetylgalactosamine) enhances cytokine secretion (TNFα, IL-8, IL-10) induced by TLR 7/8 stimulation specifically in CD1c+ DCs.","method":"Transcriptomic analysis, flow cytometry across tissues, antibody internalization assay, bivalent ligand stimulation with cytokine measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional internalization assay and ligand-triggered cytokine enhancement, transcriptomic confirmation, single lab","pmids":["29755453"],"is_preprint":false},{"year":2013,"finding":"Inhibition of p38-MK2 signaling in circulating CD1c+ myeloid DCs markedly increases IL-12 secretion, which is opposite to its effect in monocyte-derived DCs where p38 inhibition ablates IL-12. In both DC types, p38 inhibition suppresses IL-10. This differential regulation was confirmed at the transcriptional level and does not involve differential Rsk kinase phosphorylation.","method":"p38 inhibitors (BIRB0796, SB203580) applied to purified circulating myDC and moDC, cytokine measurement, transcriptional analysis, MAPK pathway interrogation","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with two inhibitors and transcriptional validation, single lab","pmids":["23901045"],"is_preprint":false},{"year":2015,"finding":"CD1c+ DCs are recruited and retained in the renal tubulointerstitium via a fractalkine-CX3CR1-dependent mechanism. CD1c+ DCs are identified as the predominant source of profibrotic TGF-β in the renal DC compartment and the highest expressors of CX3CR1. Interferon-γ and TNF-α-activated PTECs upregulate fractalkine, which mediates chemotaxis and adhesion of CD1c+ DCs.","method":"Immunohistochemistry of kidney biopsies, chemotaxis assays with fractalkine blocking, adhesion assays to activated PTECs, cytokine-induced PTEC fractalkine expression","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemotaxis and adhesion assays with fractalkine blocking, colocalization in human tissue, single lab","pmids":["25587706"],"is_preprint":false},{"year":2022,"finding":"Hypoxic human proximal tubular epithelial cells (PTECs) undergo ferroptosis and activate NLRP3 inflammasome signaling in CD1c+ DCs, leading to IL-1β and IL-18 production. Ferroptosis inhibitor ferrostatin-1 reduces PTEC death; VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inhibitor) attenuate IL-1β/IL-18 in CD1c+ DC-PTEC co-cultures. In situ, CD1c+ DCs with active inflammasome (ASC) specks colocalize with ferroptotic PTECs in fibrotic kidney tissue.","method":"In vitro hypoxia model, ferroptosis inhibitor, NLRP3 and caspase-1/4 inhibitors in co-cultures, cytokine measurement, immunolabeling of human fibrotic kidney tissue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitors defining pathway in vitro confirmed by in situ colocalization in human tissue, single lab","pmids":["36030251"],"is_preprint":false},{"year":2013,"finding":"CD1c expression on antigen-presenting cells synergistically enhances alpha-galactosylceramide (α-GalCer)-dependent activation of human iNKT cells by CD1d, beyond presenting α-GalCer as a weak agonist itself. Primary human B cells expressing CD1c induced stronger iNKT cell responses to α-GalCer than the CD1c-negative subset, and anti-CD1c antibody inhibited iNKT cell cytokine secretion.","method":"α-GalCer stimulation of iNKT cells with CD1c+ and CD1c- APCs, anti-CD1c blocking antibody, primary B cell subset comparison","journal":"Cancer immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking antibody with primary cells and defined ligand, single lab","pmids":["23885215"],"is_preprint":false}],"current_model":"CD1c is an MHC class I-like antigen-presenting molecule that surveys early endosomal/non-lysosomal compartments (directed by a cytoplasmic tail tyrosine-based internalization motif) to load and present diverse self and foreign lipid antigens—including mycobacterial phosphomycoketides, isoprenoid glycolipids, lipopeptides, methyl-lysophosphatidic acids, and cholesteryl esters—to αβ and γδ T cells via a ternary CD1c–lipid–TCR interaction; some antigens are processed by cellular deglycosylation before presentation, TCR autoreactivity can occur through sequestration of small lipids within the closed CD1c portal, and CD1c also regulates NKT responses by competitively binding the inhibitory receptor ILT4 away from CD1d."},"narrative":{"mechanistic_narrative":"CD1c is an MHC class I-like, beta2-microglobulin-associated antigen-presenting molecule that surveys non-lysosomal compartments to capture and display lipid antigens to T cells [PMID:2447586, PMID:10899914]. Originally defined as a CD1 family glycoprotein expressed on a subset of B cells and myeloid dendritic cells [PMID:2447586, PMID:3260523], CD1c presents a structurally diverse repertoire of foreign and self lipids—including mycobacterial isoprenoid glycolipids and mannosyl-beta1-phosphomycoketides, lipopeptides, leukemia-associated methyl-lysophosphatidic acids, and self cholesteryl esters/steryl glycosides—to alphabeta and Vdelta1 gammadelta T cells [PMID:10786796, PMID:18022562, PMID:19468063, PMID:24935257, PMID:26884207]. Its intracellular trafficking is directed by a cytoplasmic-tail tyrosine-based internalization motif that targets CD1c to early/late endosomes rather than lysosomes; deleting the tail abolishes most intracellular localization, and rerouting CD1c to lysosomes destroys certain antigens, establishing that CD1c loads antigen along an early endosomal/non-lysosomal pathway distinct from the lysosome-dependent CD1b route [PMID:10899914, PMID:10903726, PMID:19468063]. Presentation can require cellular processing: mannosylphosphomycoketide antigens are deglycosylated before recognition, a model reinforced by hydrolysis-resistant analogs that alter T-cell but not CD1c recognition [PMID:23530121, PMID:34536421]. Crystallographic and biophysical studies define a ternary CD1c–lipid–TCR interaction in which the A' pocket accommodates the alkyl chain and lipid occupancy stabilizes specific conformations of the alpha1/alpha2 helices that form the TCR footprint; autoreactivity arises when small self lipids are fully sequestered within the closed portal, allowing TCRs to bind the CD1c surface directly [PMID:25298532, PMID:26884207, PMID:29531339]. Beyond antigen display, CD1c binds the inhibitory receptor ILT4 with higher affinity than CD1d and acts as a sink that relieves ILT4-mediated inhibition of CD1d-restricted NKT responses [PMID:22888216, PMID:23885215]. CD1c also marks a functionally distinct myeloid DC subset that cross-primes CD8+ T cells and drives Th1/Th17 polarization through context-dependent cytokine programs [PMID:23794066, PMID:25765676, PMID:28878767]. CD1c-restricted T cells contribute to antimicrobial immunity against Mycobacterium tuberculosis [PMID:10786796, PMID:15611286] and to recognition of CD1c+ leukemia cells [PMID:24935257].","teleology":[{"year":1987,"claim":"Established CD1c as a distinct member of an MHC class I-like, beta2-microglobulin-associated gene family, defining the molecular class of the protein before any function was known.","evidence":"Gene transfection into mouse cells, genomic/cDNA sequencing, and monoclonal antibody recognition","pmids":["2447586"],"confidence":"High","gaps":["Did not define ligand or antigen-presenting function","No cell-type expression pattern established"]},{"year":1988,"claim":"Defined the cellular expression niche of CD1c—restricted to B-cell subsets and inducible by BCR activation—linking the molecule to adaptive immune cell populations.","evidence":"Flow cytometry, ultrastructural analysis, and in vitro B-cell activation","pmids":["3260523"],"confidence":"High","gaps":["Functional role on B cells not addressed","Did not characterize dendritic cell expression"]},{"year":1996,"claim":"Demonstrated that CD1c is a functional antigen-presenting molecule for mycobacterial lipids, recognized in a TAP- and DM-independent manner, distinguishing it from peptide-presenting MHC.","evidence":"CD1c-restricted T cell line cytotoxicity assays with TAP/DM independence testing and antibody blocking","pmids":["8816382"],"confidence":"High","gaps":["Chemical identity of antigens not defined","Basis of autoreactivity to CD1c itself unexplained"]},{"year":2000,"claim":"Identified the chemical class of CD1c foreign antigens (isoprenoid glycolipids/phosphodolichols) and showed clinical relevance via responses in M. tuberculosis-infected subjects.","evidence":"Mass spectrometry lipid identification plus CD1c-restricted T cell assays and ex vivo responses","pmids":["10786796"],"confidence":"High","gaps":["Bacterial biosynthetic origin of antigens not yet established","Stereochemical requirements unknown"]},{"year":2000,"claim":"Defined the trafficking and antigen-loading pathway of CD1c, showing surface/early-endosomal distribution governed by a tail tyrosine motif and a lysosome-independent route distinct from CD1b.","evidence":"Subcellular fractionation, confocal microscopy, tail-deletion mutagenesis, acidification inhibition, and GPI-reanchoring with functional T cell assays","pmids":["10899914","10903726"],"confidence":"High","gaps":["Molecular machinery directing endosomal sorting not identified","Lipid loading chaperones unknown"]},{"year":2004,"claim":"Pinpointed the mycobacterial polyketide synthase pks12 as the genetic source of CD1c mycoketide antigens, providing pathogen-specific biosynthetic grounding for antigen production.","evidence":"Genetic deletion/complementation of pks12 in M. tuberculosis with biochemistry and T cell activation","pmids":["15611286"],"confidence":"High","gaps":["Host processing of these antigens not yet addressed","Structural basis of CD1c binding unknown"]},{"year":2007,"claim":"Established the stereochemical fine specificity of CD1c-restricted T cells, showing recognition of bacteria-specific S-configuration methyl-branched lipid patterns matched to pks12 output.","evidence":"Synthetic stereorandom vs stereospecific phosphomycoketide analogs in T cell assays","pmids":["18022562"],"confidence":"High","gaps":["Structural docking of antigen in CD1c not determined","TCR contribution to stereoselectivity unresolved"]},{"year":2009,"claim":"Showed CD1c presents lipopeptides and that proper presentation depends on its early-endosomal trafficking, since lysosomal rerouting destroys the antigen—mechanistically defining where CD1c surveys.","evidence":"Synthetic lipopeptide assays with CD1c tail mutation to redirect trafficking and protease inhibition","pmids":["19468063"],"confidence":"High","gaps":["Range of compartments surveyed beyond endosomes unclear","Loading mechanism for lipopeptides not defined"]},{"year":2011,"claim":"Catalogued the endogenous self-lipid cargo of CD1c by direct biochemistry, implicating ER/Golgi/secretory as well as endocytic compartments in CD1c surveillance.","evidence":"Affinity purification of CD1c and mass spectrometry of bound lipids with specificity controls","pmids":["21900247"],"confidence":"High","gaps":["Functional/antigenic role of individual self-lipids not tested here","Compartmental loading routes inferred, not directly shown"]},{"year":2012,"claim":"Revealed an antigen-presentation-independent function: CD1c binds the inhibitory receptor ILT4 with higher affinity than CD1d and acts as a sink to enhance CD1d-restricted NKT recognition.","evidence":"Binding affinity measurements with CD1c gain/loss-of-function and NKT co-culture assays","pmids":["22888216"],"confidence":"Medium","gaps":["Single lab; structural basis of CD1c-ILT4 interaction not defined","In vivo relevance of the ILT4 sink mechanism untested"]},{"year":2013,"claim":"Provided direct biophysical and processing evidence for the ternary CD1c-lipid-TCR interaction, showing antigen deglycosylation generates the recognized phosphomycoketide neoepitope.","evidence":"CD1c tetramers, cell-free antigen-processing systems, and ex vivo human T cell detection","pmids":["23530121"],"confidence":"High","gaps":["Identity of host deglycosylating enzyme not established","Generality of processing across CD1c antigens unknown"]},{"year":2013,"claim":"Defined CD1c+ myeloid DCs as a functionally specialized subset that cross-primes CD8 T cells and polarizes T-helper responses through distinctive, often IL-12-independent, cytokine programs.","evidence":"Purified blood/tissue DC subset functional assays, TLR stimulation, cross-presentation and priming assays, IL-12 neutralization and an IL-12-deficient patient","pmids":["23794066","23562160","25765676","22678905"],"confidence":"High","gaps":["Relationship between CD1c lipid presentation and these DC effector functions unclear","Molecular basis of subset-specific cytokine wiring incomplete"]},{"year":2014,"claim":"Extended CD1c antigen repertoire to a tumor-associated self lipid (methyl-lysophosphatidic acid), demonstrating CD1c-restricted T cells can recognize and kill CD1c+ leukemia in vitro and in vivo.","evidence":"Lipid biochemistry, CD1c-blocked cytotoxicity, and xenograft mouse model","pmids":["24935257"],"confidence":"High","gaps":["Mechanism of mLPA accumulation in leukemia not defined","Therapeutic translatability untested"]},{"year":2014,"claim":"Solved the structural basis of CD1c antigen presentation, mapping the A' pocket binding of the mycoketide chain and identifying diverse alpha1/alpha2 helix residues used by structurally varied TCRs.","evidence":"X-ray crystallography of CD1c-PM, surface plasmon resonance across multiple TCRs, and CD1c/TCR mutagenesis","pmids":["25298532"],"confidence":"High","gaps":["No single archetypical TCR footprint—rules of recognition incomplete","Self-lipid complexes not crystallized here"]},{"year":2016,"claim":"Showed CD1c serves Vdelta1+ gammadelta TCRs directly and discriminates permissive from non-permissive lipid ligands, broadening CD1c's role across T cell lineages.","evidence":"CD1c tetramer staining with Vdelta selection and Vdelta1 domain mutagenesis across diverse lipids","pmids":["26755823"],"confidence":"High","gaps":["Physiological gammadelta ligand in vivo unidentified","Structural basis of gammadelta-CD1c contact not solved"]},{"year":2016,"claim":"Linked CD1c conformation to autoreactivity, showing self-lipid occupancy (cholesteryl esters, acylated steryl glycosides) stabilizes conformations forming a footprint for self-reactive TCRs.","evidence":"2.4 Å crystal structure, molecular dynamics, lipid loading, and TCR binding assays","pmids":["26884207"],"confidence":"High","gaps":["Physiological abundance of these self-lipids on APCs unclear","Consequences of autoreactivity in vivo not defined"]},{"year":2018,"claim":"Resolved the structural mechanism of CD1c TCR polyspecificity, showing TCRs dock over the closed portal without contacting fully sequestered small self lipids—explaining lipid-permissive autoreactivity.","evidence":"CD1c tetramer staining with diverse self lipids and crystallography of a TCR-CD1c complex","pmids":["29531339"],"confidence":"High","gaps":["Functional threshold separating tolerance from autoreactivity unknown","Role of portal sequestration for larger antigens unaddressed"]},{"year":2021,"claim":"Reinforced the antigen-processing model by showing hydrolysis-resistant phosphomycoketide analogs bind CD1c normally but are recognized differently by T cells, indicating glycolipid hydrolysis during presentation.","evidence":"Synthetic analogs, crystallography of CD1c-analog complexes, and T cell assays","pmids":["34536421"],"confidence":"High","gaps":["Identity and localization of the responsible hydrolase still unknown","Kinetics of processing during presentation undefined"]},{"year":2016,"claim":"Identified post-transcriptional control of CD1c expression by miR-381-3p as part of an IL-10-driven immunosuppressive circuit during mycobacterial infection.","evidence":"Luciferase 3'-UTR reporter, miR-381-3p inhibition in BCG-infected DCs, and TB patient DC analysis","pmids":["27296666"],"confidence":"Medium","gaps":["Single lab; in vivo causal role of the circuit not established","Other regulators of CD1c expression not surveyed here"]},{"year":null,"claim":"How CD1c lipid surveillance, conformational autoreactivity, and the effector functions of CD1c+ DCs are mechanistically integrated in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified host enzyme performing antigen deglycosylation","Connection between CD1c lipid presentation and CD1c+ DC cytokine programs unestablished","In vivo significance of ILT4-sink and autoreactivity not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,10,11,12,22,27]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[16,23,26,28]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[4,16,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,16,17,22]}],"complexes":[],"partners":["B2M","ILT4","TRAV/TRBV TCR","TRDV1 (VDELTA1 TCR)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P29017","full_name":"T-cell surface glycoprotein CD1c","aliases":[],"length_aa":333,"mass_kda":37.7,"function":"Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells","subcellular_location":"Cell membrane; Endosome membrane; Lysosome","url":"https://www.uniprot.org/uniprotkb/P29017/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD1C","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD1C","total_profiled":1310},"omim":[{"mim_id":"615161","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ BETA-2; HLA-DQB2","url":"https://www.omim.org/entry/615161"},{"mim_id":"614893","title":"IMMUNODEFICIENCY 32A; IMD32A","url":"https://www.omim.org/entry/614893"},{"mim_id":"613503","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ ALPHA-2; HLA-DQA2","url":"https://www.omim.org/entry/613503"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":121.2}],"url":"https://www.proteinatlas.org/search/CD1C"},"hgnc":{"alias_symbol":[],"prev_symbol":["CD1"]},"alphafold":{"accession":"P29017","domains":[{"cath_id":"3.30.500.10","chopping":"27-202","consensus_level":"high","plddt":95.0494,"start":27,"end":202},{"cath_id":"2.60.40.10","chopping":"208-296","consensus_level":"high","plddt":92.7517,"start":208,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29017","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29017-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29017-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD1C","jax_strain_url":"https://www.jax.org/strain/search?query=CD1C"},"sequence":{"accession":"P29017","fasta_url":"https://rest.uniprot.org/uniprotkb/P29017.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29017/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29017"}},"corpus_meta":[{"pmid":"10786796","id":"PMC_10786796","title":"CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection.","date":"2000","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10786796","citation_count":342,"is_preprint":false},{"pmid":"32610077","id":"PMC_32610077","title":"Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells.","date":"2020","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/32610077","citation_count":291,"is_preprint":false},{"pmid":"23794066","id":"PMC_23794066","title":"Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23794066","citation_count":278,"is_preprint":false},{"pmid":"17332250","id":"PMC_17332250","title":"Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17332250","citation_count":172,"is_preprint":false},{"pmid":"25687281","id":"PMC_25687281","title":"Circulating precursors of human CD1c+ and CD141+ dendritic cells.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25687281","citation_count":170,"is_preprint":false},{"pmid":"8816382","id":"PMC_8816382","title":"CD1c restricts responses of mycobacteria-specific T cells. 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CD1c has a duplicated form of a conserved 5'-untranslated exon. The genes were identified by transfection into mouse cells, which then expressed the surface antigens recognized by cluster-defining monoclonal antibodies.\",\n      \"method\": \"Gene transfection into mouse cells, genomic DNA sequencing, cDNA cloning, monoclonal antibody recognition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct gene identification, expression in transfectants, structural analysis with mutagenesis-level domain mapping; foundational paper\",\n      \"pmids\": [\"2447586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CD1c expression is restricted to a subset of B cells (mantle zone B cells in lymphoid organs and ~50% of peripheral blood/spleen B cells), whereas CD1a and CD1b are not expressed on B or T cells. CD1c expression is upregulated on B cells upon BCR activation and induced de novo on previously CD1c-negative B cells in vitro, while activated T cells remain CD1c-negative.\",\n      \"method\": \"Flow cytometry, in vitro B cell activation, immunofluorescence, ultrastructural analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (flow cytometry, ultrastructure, in vitro activation), replicated pattern across tissues\",\n      \"pmids\": [\"3260523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD1c molecules on target cell surfaces can serve as recognition structures for a subset of gamma/delta T cells. Only rare peripheral blood gamma/delta clones (using Vdelta1/J1 rearrangement) interact with targets via a CD1c-dependent recognition pathway, indicating CD1c does not have a broad contribution to the peripheral gamma/delta T cell repertoire.\",\n      \"method\": \"Cytotoxicity assays using 43 cloned and 11 polyclonal gamma/delta T cell lines; blocking with anti-CD1c antibody\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with antibody in multiple cell lines, single lab\",\n      \"pmids\": [\"1690662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD1c functions as an antigen-presenting molecule that restricts mycobacteria-specific T cell responses. CD1c-restricted T cell lines recognize protease-resistant mycobacterial lipid antigens in an MHC-unrestricted, TAP-1/2- and DMA/B-independent manner. A subpopulation of T cells also shows direct cytotoxicity toward CD1c-expressing target cells without mycobacterial antigen, indicating autoreactivity to CD1c itself.\",\n      \"method\": \"T cell line derivation from donor blood, cytotoxicity assays, MHC-blocking, TAP/DM independence testing, clonal analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (cytotoxicity, cytokine, blocking), replicated across clones and donors\",\n      \"pmids\": [\"8816382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD1c presents an evolutionarily conserved family of isoprenoid glycolipids including mycobacterial hexosyl-1-phosphoisoprenoids and mannosyl-beta1-phosphodolichols. T cell recognition via CD1c and the T cell antigen receptor was demonstrated for these lipid antigens, with T cell responses observed in M. tuberculosis-infected subjects but not naive controls.\",\n      \"method\": \"CD1c-restricted T cell line recognition assays, mass spectrometry-based lipid identification, ex vivo T cell responses from infected vs. naive subjects\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical identification of antigens combined with functional T cell assays and clinical validation\",\n      \"pmids\": [\"10786796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD1c distributes predominantly at the cell surface with minimal intracellular accumulation in human dendritic cells, contrasting with CD1b which accumulates in lysosomal MHC class II compartments. Intracellular CD1c localizes to early and late endosomes, not lysosomes. Deletion of the cytoplasmic tail tyrosine-based internalization motif of CD1c abolishes most intracellular localization. CD1c-mediated antigen presentation is resistant to endosomal acidification inhibitors and is independent of endosomal localization, distinguishing it mechanistically from CD1b.\",\n      \"method\": \"Subcellular fractionation, confocal microscopy, tail-deletion mutagenesis, pharmacological inhibition of endosomal acidification, T cell functional assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct localization experiments with mutagenesis and functional validation in same study\",\n      \"pmids\": [\"10899914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD1c-restricted double-negative (DN) T cells from SLE patients provide help to CD1c+ B cells for IgG production and isotype switching. Anti-CD1c blocking antibodies inhibit DN T cell-induced IgG production, and anti-IL-4 neutralization also inhibits IgG production, correlating with IL-4 production by DN T cells from SLE patients. DN T cells from healthy donors induced only IgM with CD1c+ B cells.\",\n      \"method\": \"T cell-B cell co-culture, antibody blocking (anti-CD1c, anti-IL-4), cytokine measurement (IL-4, IFN-gamma)\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal blocking experiments and cytokine measurement, single lab\",\n      \"pmids\": [\"11046069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GPI-reanchored CD1c (CD1c.DAF) maintains the ability to present mycobacterial antigens to CD1c-restricted T cells as efficiently as native CD1c, whereas GPI-reanchored CD1b is less efficient than native CD1b. This demonstrates that CD1c and CD1b have distinct, non-overlapping antigen-presenting pathways, with CD1c accessing antigen-loading compartments that do not require the cytoplasmic tail-directed trafficking used by CD1b.\",\n      \"method\": \"GPI-reanchored fusion protein engineering, cytotoxicity and cytokine release assays with CD1c-restricted and CD1b-restricted T cell lines, PI-PLC treatment to confirm GPI anchoring\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — engineered GPI variants with functional reconstitution and direct comparison between isoforms\",\n      \"pmids\": [\"10903726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The M. tuberculosis gene pks12 encodes a polyketide synthase responsible for producing CD1c-presented mycoketide antigens (C30-34 branched alkane lipids). Genetic deletion and complementation of pks12 demonstrated it is necessary for antigen production. The lipid moiety distinguishes mycobacterial antigens from mammalian mannosyl-beta1-phosphodolichols and is required for activation of CD1c-restricted T cells.\",\n      \"method\": \"Metabolic radiolabeling, mass spectrometry, genetic deletion and complementation of pks12 in M. tuberculosis, T cell activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic epistasis (deletion/complementation) combined with biochemical characterization and functional T cell assays\",\n      \"pmids\": [\"15611286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD1c-restricted, glycolipid-specific T cells accumulate in inflamed thyroid tissue during Graves' disease and Hashimoto's thyroiditis but were not detected in peripheral blood. Polyclonal thyroid-derived lymphocytes and T cell lines lyse targets in a CD1c-dependent manner. CD1c is expressed on CD83+ dendritic cells and on CD20+ IgD+ mantle zone B cells within thyroid lymphoid follicles.\",\n      \"method\": \"Immunofluorescence of thyroid tissue, ex vivo T cell line derivation, cytotoxicity assays with CD1c-blocking antibodies\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays with CD1c blocking, tissue localization, single lab\",\n      \"pmids\": [\"15749918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD1c presentation of synthetic mannosyl phosphomycoketide antigens requires both a phosphate group and a beta-linked mannose unit. T cell responses show preference for C30-34 lipid units with methyl branches in the S-configuration, matching the stereospecific output of mycobacterial pks12. Stereorandom branching is insufficient for T cell activation, indicating that CD1c-restricted T cells detect a bacterial-specific polyketide lipid pattern.\",\n      \"method\": \"Synthetic chemistry (stereorandom and stereospecific analogs), T cell activation assays with CD1c-restricted T cell lines\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic structure-activity relationship using synthetic analogs with defined stereochemistry, functional T cell readout\",\n      \"pmids\": [\"18022562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD1c can present a lipopeptide antigen (N-acyl glycine dodecamer, lipo-12) to human T cells in a manner dependent on the acyl linkage, peptide length, and sequence. Unlike CD1b-presented antigens that require lysosomal processing, rerouting CD1c to lysosomes by mutating its cytoplasmic tail sequences reduces lipo-12 presentation. This demonstrates that CD1c surveys early endosomal/non-lysosomal pathways and that certain antigens are destroyed in lysosomes.\",\n      \"method\": \"Synthetic lipopeptide T cell activation assays, CD1c tail mutation to redirect trafficking, protease inhibitor treatment, CD1c transfection\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of CD1c tail, pharmacological manipulation, reconstitution with synthetic antigen, multiple mechanistic controls\",\n      \"pmids\": [\"19468063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mass spectrometry analysis of highly purified CD1c protein identified 11 novel self-lipids specifically loaded into CD1c's lipid-binding site, including lipids distinct from those presented by CD1d. The distinct but overlapping lipid populations identified for each CD1 family member imply that CD1c surveys specific endoplasmic reticulum, Golgi, and/or secretory compartments in addition to endocytic compartments.\",\n      \"method\": \"Affinity purification of CD1c protein, mass spectrometry with rigorous controls for specificity of lipid binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry with purified protein and rigorous controls establishing specific lipid binding\",\n      \"pmids\": [\"21900247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD1c expression and function in human B cells are regulated by activation signals. BCR activation significantly upregulates CD1c expression particularly on marginal zone-like B cells, while CD40L stimulation downregulates CD1c. The CD40L-induced downregulation of CD1c correlates with diminished retinoic acid receptor alpha (RARα) response gene expression, which is reversed by RARα agonists. BCR-induced CD1c upregulation is RAR-independent.\",\n      \"method\": \"In vitro B cell activation, flow cytometry, RARα agonist treatment, gene expression analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple activation conditions and pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"21451111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD1c can interact specifically with immunoglobulin-like transcript 4 (ILT4) with higher affinity than CD1d. Upregulation of CD1c expression enhances NKT cell recognition of CD1d, while downregulation reduces CD1d recognition. The proposed mechanism is that CD1c acts as a sink for the inhibitory receptor ILT4, reducing ILT4-mediated inhibition of CD1d.\",\n      \"method\": \"Binding affinity measurements, CD1c overexpression and knockdown, NKT cell co-culture functional assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding data combined with gain/loss-of-function experiments, single lab\",\n      \"pmids\": [\"22888216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In rhesus macaques vaccinated with BCG, the major T cell response to glucose monomycolate (GMM), a mycolate-containing glycolipid normally thought to be CD1b-restricted in humans, is restricted by CD1c rather than CD1b. GMM-specific CD1c-restricted T cells produced IFN-γ and TNF-α, and could extravasate to sites of infection where CD1c+ cells accumulated.\",\n      \"method\": \"BCG vaccination of macaques, T cell proliferation assays with CD1b/CD1c blocking antibodies, cytokine analysis, immunohistochemistry of infection sites\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with antibody blocking and functional characterization, single lab\",\n      \"pmids\": [\"23132493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD1c-restricted T cells recognize C32 phosphomycoketide (PM) as a CD1c-presented antigen, with antigen binding and presentation requiring the unusual mycobacteria-specific methyl-branched lipid pattern from pks12. Antigen processing by dendritic cells and B cells generates a deglycosylated phosphomycoketide neoepitope — cell-free systems showed recognition only of the deglycosylated form. CD1c tetramers loaded with PM stain T cell receptors directly, providing biophysical evidence for a ternary CD1c-lipid-TCR interaction, and detected polyclonal T cell responses ex vivo in human peripheral blood.\",\n      \"method\": \"CD1c tetramer staining, cell-free antigen presentation systems, T cell activation assays, ex vivo human blood T cell detection\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with tetramers, cell-free systems showing processing, direct TCR binding, and ex vivo validation\",\n      \"pmids\": [\"23530121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human CD1c+ myeloid DCs (mDC1) are the only human DC subset to secrete high amounts of IL-12p70 (requiring combinational TLR stimulation), and they are fully equipped to cross-prime naive CD8+ T cells, inducing the highest levels of cytotoxic molecules due to IL-12 production. CD1c+ DCs required different TLR ligand combinations for cross-presentation compared to BDCA-3+ DCs.\",\n      \"method\": \"Purification of blood DC subsets, TLR stimulation, intracellular cytokine staining, naive CD8+ T cell priming assays, cross-presentation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays across DC subsets, replicated comparisons\",\n      \"pmids\": [\"23794066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD1c+ blood myeloid DCs respond to E. coli with an immunoregulatory rather than inflammatory phenotype: they produce high IL-10 and regulatory molecules IDO and soluble CD25, but only low TNF, IL-6, and IL-12. E. coli-activated CD1c+ DCs suppress T cell proliferation in an IL-10-dependent manner, distinguishing them functionally from monocyte-derived DCs.\",\n      \"method\": \"Purified blood DC stimulation with E. coli, multiplex cytokine measurement, T cell suppression assays with IL-10 neutralization\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cytokine endpoints with mechanistic neutralization, single lab\",\n      \"pmids\": [\"22678905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lung-tissue-resident CD1c+ DCs, but not CD141+ DCs, drive CD103 expression on CD8+ T cells and promote CD8+ T cell accumulation in lung epithelia. CD1c+ DC induction of CD103 expression is dependent on membrane-bound TGF-β1.\",\n      \"method\": \"Human lung tissue DC isolation, humanized mouse model, in vitro and in vivo CD8+ T cell priming assays, TGF-β1 blocking/neutralization\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo experiments with cytokine-blocking mechanistic validation, both human tissue and humanized mouse model\",\n      \"pmids\": [\"23562160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD1c+ blood myeloid DCs stimulate a strong IL-12-independent IFN-γ (Th1) response, in contrast to monocyte-derived DCs which induce IL-12-dependent Th1 responses. This was validated in a patient with severely impaired IL-12 production, whose CD1c+ DCs induced normal Th1 responses while his moDC failed. CD1c+ DCs showed minimal upregulation of inflammatory-associated genes compared to moDC.\",\n      \"method\": \"IL-12 neutralization in co-culture assays, patient with IL-12 deficiency as natural experiment, microarray gene expression analysis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway dissection with neutralizing antibody plus natural genetic experiment (IL-12-deficient patient), corroborated by transcriptomics\",\n      \"pmids\": [\"25765676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD1c+ myeloid DCs acquire high retinoic acid-producing capacity (RALDH2 expression and ALDH activity) in response to vitamin D3 in the presence of GM-CSF, via a p38-dependent pathway. RALDH2-high CD1c+ DCs stimulate naive CD4+ T cells to express gut-homing molecules and produce Th2 cytokines in an RA-dependent manner. TLR ligands or TNF abrogate this ALDH activity.\",\n      \"method\": \"RALDH2 mRNA quantification, ALDH activity assays, vitamin D3 stimulation, p38 inhibition, T cell gut-homing assays with RA blockade\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay with pharmacological inhibitors and functional T cell readout, single lab\",\n      \"pmids\": [\"23966631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD1c presents a novel class of self-lipids—methyl-lysophosphatidic acids (mLPAs)—that accumulate in leukemia cells. mLPA-specific CD1c-restricted T cells efficiently kill CD1c+ acute leukemia cells in vitro and protect immunodeficient mice against CD1c+ human leukemia cells in vivo.\",\n      \"method\": \"Lipid biochemistry to identify mLPA, T cell recognition assays with CD1c-blocking, in vitro cytotoxicity, xenograft mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel antigen identification plus in vitro and in vivo functional validation with blocking controls\",\n      \"pmids\": [\"24935257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of CD1c with phosphomycoketide (PM) shows the A' pocket accommodates the mycoketide alkyl chain, with the phosphate head-group shifted ~6 Å compared to mannosyl-β1-PM. Six human TCRs show high-to-moderate affinity interactions with CD1c-mycoketide complexes. Mutagenesis of CD1c reveals residues in both α1 and α2 helices involved in TCR recognition, with no single archetypical binding footprint shared among CD1c-reactive TCRs.\",\n      \"method\": \"X-ray crystallography of CD1c-PM complex, surface plasmon resonance (TCR binding affinity), site-directed mutagenesis of CD1c residues, TCR CDR mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and direct binding measurements across multiple TCRs\",\n      \"pmids\": [\"25298532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Langerin expression is rapidly induced on CD1c+ DCs by serum or TGF-β via an ALK-3-dependent pathway when DCs are isolated from blood and cultured. Langerin is not expressed on freshly isolated CD1c+ blood DCs but appears on CD1c+ DCs in tissues, indicating tissue microenvironment drives this phenotypic differentiation.\",\n      \"method\": \"Flow cytometry of tissue and blood DC subsets, TGF-β stimulation, ALK-3 inhibition, stem cell transplantation models\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with ALK-3 inhibitor and in vitro induction assay, single lab\",\n      \"pmids\": [\"25516751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD1c+ DCs can differentiate into Langerhans cell-like cells with high langerin expression, Birbeck granules, EpCAM, and E-cadherin when cultured with GM-CSF, TGF-β, and BMP7, making them far more LC-like than monocytes under the same conditions.\",\n      \"method\": \"In vitro differentiation assay with defined cytokine combinations, flow cytometry, electron microscopy for Birbeck granules\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined culture system with multiple readouts including ultrastructure, single lab\",\n      \"pmids\": [\"25352125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD1c tetramers loaded with phosphomycoketide bind Vδ1+ γδ TCRs with biophysical evidence for a direct CD1c–γδ TCR interaction. Mutational analysis demonstrates a role of the Vδ1 domain during recognition. CD1c-reactive γδ TCRs also bind CD1c complexes with diverse lipids (lysophosphatidylcholine, sulfatide, mannosyl-phosphomycoketide) but not lipopeptide ligands, revealing permissive and non-permissive lipid determinants.\",\n      \"method\": \"CD1c tetramer staining with Vδ subtype selection, TCR binding assays, Vδ1 domain mutagenesis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biophysical tetramer binding with mutagenesis identifying domain requirements, multiple lipid ligands tested\",\n      \"pmids\": [\"26755823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of CD1c at 2.4 Å reveals an extended ligand binding groove and a substantially different conformation from previously known CD1c structures. Computational simulations predict cholesteryl esters (CE) and acylated steryl glycosides (ASG) as CD1c ligands. Binding of CE and ASG to CD1c enables binding of human CD1c self-reactive T cell receptors, demonstrating that lipid occupancy stabilizes specific CD1c conformations that provide a footprint for autoreactive TCR binding.\",\n      \"method\": \"X-ray crystallography (2.4 Å), molecular dynamics simulations, lipid-loading assays, T cell receptor binding experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus molecular dynamics plus functional TCR binding validation in same study\",\n      \"pmids\": [\"26884207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human T cells frequently stain with CD1c tetramers carrying diverse self lipids, with TCRs showing extreme polyspecificity — autoreactivity occurs with CD1c loaded with numerous, chemically diverse self lipids. Crystal structure shows the TCR binds over the closed portal surface of CD1c where lipids normally protrude, with the TCR failing to contact lipids because they are fully sequestered within CD1c. Small lipid size is identified as a determinant of autoreactive T cell responses.\",\n      \"method\": \"CD1c tetramer staining with diverse lipids, X-ray crystallography of TCR-CD1c complex, mutational analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of TCR-CD1c complex directly reveals the sequestration mechanism, validated across multiple TCRs and lipids\",\n      \"pmids\": [\"29531339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MiR-381-3p binds the 3'-UTR of the CD1c gene and suppresses CD1c mRNA expression in M. tuberculosis-infected dendritic cells. Inhibition of miR-381-3p in BCG-infected DCs reverses suppression of CD1c expression and promotes T cell responses against BCG. IL-10 upregulates miR-381-3p as part of an immunosuppressive circuit.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay (bioinformatic prediction + validation), miR-381-3p inhibitor in BCG-infected DCs, T cell co-culture assays, in vivo miR-381-3p expression in TB patient DCs\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay for 3'-UTR targeting plus gain/loss-of-function in primary cells with functional T cell readout, single lab\",\n      \"pmids\": [\"27296666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"iC3b inhibits differentiation of CD11b+ monocytes into CD1c-expressing dendritic cell precursors. This inhibition is mediated through CD11b (the iC3b receptor) as an anti-CD11b blocking antibody reverses the effect. iC3b also inhibits IL-12p70 production and CD80/CD40 expression, causing a temporary arrest of DC differentiation.\",\n      \"method\": \"GM-CSF-induced monocyte differentiation in vitro, iC3b treatment, anti-CD11b blocking antibody, keratome biopsy-derived dermal cell analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro differentiation assay with receptor blocking antibody identifying mechanistic pathway, single lab\",\n      \"pmids\": [\"12713585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystallographic studies of CD1c complexes with three hydrolysis-resistant MPM analogs (including difluoromethylene-modified MPM-3) show anchoring of the lipid tail and phosphate group highly comparable to native MPM, but with considerable conformational flexibility for the mannose head group. MPM-3, resistant to hydrolysis, shows altered recognition by T cells but not by CD1c proteins, supporting the cellular antigen processing hypothesis that glycolipid hydrolysis occurs during presentation.\",\n      \"method\": \"Synthetic chemistry, X-ray crystallography of CD1c-analog complexes, T cell activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple CD1c-ligand complexes combined with functional T cell assays supporting processing mechanism\",\n      \"pmids\": [\"34536421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human CD1c+ DCs produce IL-12p70, IL-1β, IL-6, and IL-23 in response to combined TLR stimulation and are capable of promoting both Th1 (IFN-γ) and Th17 (IL-17A, IL-17F, IL-21, IL-22) effector function in memory CD4+ T cells.\",\n      \"method\": \"Purified blood CD1c+ DC TLR stimulation (R848+LPS or poly I:C), multiplex cytokine measurement, memory CD4+ T cell co-culture with cytokine readout\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — purified primary cell functional assays with defined TLR stimuli, single lab\",\n      \"pmids\": [\"28878767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLEC10A (CD301) is identified as a specific endocytic receptor on human CD1c+ DCs. CLEC10A rapidly internalizes upon monoclonal antibody binding. A bivalent CLEC10A-specific ligand (MUC-1 peptide glycosylated with N-acetylgalactosamine) enhances cytokine secretion (TNFα, IL-8, IL-10) induced by TLR 7/8 stimulation specifically in CD1c+ DCs.\",\n      \"method\": \"Transcriptomic analysis, flow cytometry across tissues, antibody internalization assay, bivalent ligand stimulation with cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional internalization assay and ligand-triggered cytokine enhancement, transcriptomic confirmation, single lab\",\n      \"pmids\": [\"29755453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inhibition of p38-MK2 signaling in circulating CD1c+ myeloid DCs markedly increases IL-12 secretion, which is opposite to its effect in monocyte-derived DCs where p38 inhibition ablates IL-12. In both DC types, p38 inhibition suppresses IL-10. This differential regulation was confirmed at the transcriptional level and does not involve differential Rsk kinase phosphorylation.\",\n      \"method\": \"p38 inhibitors (BIRB0796, SB203580) applied to purified circulating myDC and moDC, cytokine measurement, transcriptional analysis, MAPK pathway interrogation\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with two inhibitors and transcriptional validation, single lab\",\n      \"pmids\": [\"23901045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD1c+ DCs are recruited and retained in the renal tubulointerstitium via a fractalkine-CX3CR1-dependent mechanism. CD1c+ DCs are identified as the predominant source of profibrotic TGF-β in the renal DC compartment and the highest expressors of CX3CR1. Interferon-γ and TNF-α-activated PTECs upregulate fractalkine, which mediates chemotaxis and adhesion of CD1c+ DCs.\",\n      \"method\": \"Immunohistochemistry of kidney biopsies, chemotaxis assays with fractalkine blocking, adhesion assays to activated PTECs, cytokine-induced PTEC fractalkine expression\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemotaxis and adhesion assays with fractalkine blocking, colocalization in human tissue, single lab\",\n      \"pmids\": [\"25587706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hypoxic human proximal tubular epithelial cells (PTECs) undergo ferroptosis and activate NLRP3 inflammasome signaling in CD1c+ DCs, leading to IL-1β and IL-18 production. Ferroptosis inhibitor ferrostatin-1 reduces PTEC death; VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inhibitor) attenuate IL-1β/IL-18 in CD1c+ DC-PTEC co-cultures. In situ, CD1c+ DCs with active inflammasome (ASC) specks colocalize with ferroptotic PTECs in fibrotic kidney tissue.\",\n      \"method\": \"In vitro hypoxia model, ferroptosis inhibitor, NLRP3 and caspase-1/4 inhibitors in co-cultures, cytokine measurement, immunolabeling of human fibrotic kidney tissue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitors defining pathway in vitro confirmed by in situ colocalization in human tissue, single lab\",\n      \"pmids\": [\"36030251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD1c expression on antigen-presenting cells synergistically enhances alpha-galactosylceramide (α-GalCer)-dependent activation of human iNKT cells by CD1d, beyond presenting α-GalCer as a weak agonist itself. Primary human B cells expressing CD1c induced stronger iNKT cell responses to α-GalCer than the CD1c-negative subset, and anti-CD1c antibody inhibited iNKT cell cytokine secretion.\",\n      \"method\": \"α-GalCer stimulation of iNKT cells with CD1c+ and CD1c- APCs, anti-CD1c blocking antibody, primary B cell subset comparison\",\n      \"journal\": \"Cancer immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking antibody with primary cells and defined ligand, single lab\",\n      \"pmids\": [\"23885215\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD1c is an MHC class I-like antigen-presenting molecule that surveys early endosomal/non-lysosomal compartments (directed by a cytoplasmic tail tyrosine-based internalization motif) to load and present diverse self and foreign lipid antigens—including mycobacterial phosphomycoketides, isoprenoid glycolipids, lipopeptides, methyl-lysophosphatidic acids, and cholesteryl esters—to αβ and γδ T cells via a ternary CD1c–lipid–TCR interaction; some antigens are processed by cellular deglycosylation before presentation, TCR autoreactivity can occur through sequestration of small lipids within the closed CD1c portal, and CD1c also regulates NKT responses by competitively binding the inhibitory receptor ILT4 away from CD1d.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD1c is an MHC class I-like, beta2-microglobulin-associated antigen-presenting molecule that surveys non-lysosomal compartments to capture and display lipid antigens to T cells [#0, #5]. Originally defined as a CD1 family glycoprotein expressed on a subset of B cells and myeloid dendritic cells [#0, #1], CD1c presents a structurally diverse repertoire of foreign and self lipids—including mycobacterial isoprenoid glycolipids and mannosyl-beta1-phosphomycoketides, lipopeptides, leukemia-associated methyl-lysophosphatidic acids, and self cholesteryl esters/steryl glycosides—to alphabeta and Vdelta1 gammadelta T cells [#4, #10, #11, #22, #27]. Its intracellular trafficking is directed by a cytoplasmic-tail tyrosine-based internalization motif that targets CD1c to early/late endosomes rather than lysosomes; deleting the tail abolishes most intracellular localization, and rerouting CD1c to lysosomes destroys certain antigens, establishing that CD1c loads antigen along an early endosomal/non-lysosomal pathway distinct from the lysosome-dependent CD1b route [#5, #7, #11]. Presentation can require cellular processing: mannosylphosphomycoketide antigens are deglycosylated before recognition, a model reinforced by hydrolysis-resistant analogs that alter T-cell but not CD1c recognition [#16, #31]. Crystallographic and biophysical studies define a ternary CD1c–lipid–TCR interaction in which the A' pocket accommodates the alkyl chain and lipid occupancy stabilizes specific conformations of the alpha1/alpha2 helices that form the TCR footprint; autoreactivity arises when small self lipids are fully sequestered within the closed portal, allowing TCRs to bind the CD1c surface directly [#23, #27, #28]. Beyond antigen display, CD1c binds the inhibitory receptor ILT4 with higher affinity than CD1d and acts as a sink that relieves ILT4-mediated inhibition of CD1d-restricted NKT responses [#14, #37]. CD1c also marks a functionally distinct myeloid DC subset that cross-primes CD8+ T cells and drives Th1/Th17 polarization through context-dependent cytokine programs [#17, #20, #32]. CD1c-restricted T cells contribute to antimicrobial immunity against Mycobacterium tuberculosis [#4, #8] and to recognition of CD1c+ leukemia cells [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Established CD1c as a distinct member of an MHC class I-like, beta2-microglobulin-associated gene family, defining the molecular class of the protein before any function was known.\",\n      \"evidence\": \"Gene transfection into mouse cells, genomic/cDNA sequencing, and monoclonal antibody recognition\",\n      \"pmids\": [\"2447586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define ligand or antigen-presenting function\", \"No cell-type expression pattern established\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Defined the cellular expression niche of CD1c—restricted to B-cell subsets and inducible by BCR activation—linking the molecule to adaptive immune cell populations.\",\n      \"evidence\": \"Flow cytometry, ultrastructural analysis, and in vitro B-cell activation\",\n      \"pmids\": [\"3260523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role on B cells not addressed\", \"Did not characterize dendritic cell expression\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated that CD1c is a functional antigen-presenting molecule for mycobacterial lipids, recognized in a TAP- and DM-independent manner, distinguishing it from peptide-presenting MHC.\",\n      \"evidence\": \"CD1c-restricted T cell line cytotoxicity assays with TAP/DM independence testing and antibody blocking\",\n      \"pmids\": [\"8816382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chemical identity of antigens not defined\", \"Basis of autoreactivity to CD1c itself unexplained\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the chemical class of CD1c foreign antigens (isoprenoid glycolipids/phosphodolichols) and showed clinical relevance via responses in M. tuberculosis-infected subjects.\",\n      \"evidence\": \"Mass spectrometry lipid identification plus CD1c-restricted T cell assays and ex vivo responses\",\n      \"pmids\": [\"10786796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial biosynthetic origin of antigens not yet established\", \"Stereochemical requirements unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the trafficking and antigen-loading pathway of CD1c, showing surface/early-endosomal distribution governed by a tail tyrosine motif and a lysosome-independent route distinct from CD1b.\",\n      \"evidence\": \"Subcellular fractionation, confocal microscopy, tail-deletion mutagenesis, acidification inhibition, and GPI-reanchoring with functional T cell assays\",\n      \"pmids\": [\"10899914\", \"10903726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery directing endosomal sorting not identified\", \"Lipid loading chaperones unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Pinpointed the mycobacterial polyketide synthase pks12 as the genetic source of CD1c mycoketide antigens, providing pathogen-specific biosynthetic grounding for antigen production.\",\n      \"evidence\": \"Genetic deletion/complementation of pks12 in M. tuberculosis with biochemistry and T cell activation\",\n      \"pmids\": [\"15611286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host processing of these antigens not yet addressed\", \"Structural basis of CD1c binding unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the stereochemical fine specificity of CD1c-restricted T cells, showing recognition of bacteria-specific S-configuration methyl-branched lipid patterns matched to pks12 output.\",\n      \"evidence\": \"Synthetic stereorandom vs stereospecific phosphomycoketide analogs in T cell assays\",\n      \"pmids\": [\"18022562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural docking of antigen in CD1c not determined\", \"TCR contribution to stereoselectivity unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CD1c presents lipopeptides and that proper presentation depends on its early-endosomal trafficking, since lysosomal rerouting destroys the antigen—mechanistically defining where CD1c surveys.\",\n      \"evidence\": \"Synthetic lipopeptide assays with CD1c tail mutation to redirect trafficking and protease inhibition\",\n      \"pmids\": [\"19468063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Range of compartments surveyed beyond endosomes unclear\", \"Loading mechanism for lipopeptides not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Catalogued the endogenous self-lipid cargo of CD1c by direct biochemistry, implicating ER/Golgi/secretory as well as endocytic compartments in CD1c surveillance.\",\n      \"evidence\": \"Affinity purification of CD1c and mass spectrometry of bound lipids with specificity controls\",\n      \"pmids\": [\"21900247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional/antigenic role of individual self-lipids not tested here\", \"Compartmental loading routes inferred, not directly shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed an antigen-presentation-independent function: CD1c binds the inhibitory receptor ILT4 with higher affinity than CD1d and acts as a sink to enhance CD1d-restricted NKT recognition.\",\n      \"evidence\": \"Binding affinity measurements with CD1c gain/loss-of-function and NKT co-culture assays\",\n      \"pmids\": [\"22888216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of CD1c-ILT4 interaction not defined\", \"In vivo relevance of the ILT4 sink mechanism untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided direct biophysical and processing evidence for the ternary CD1c-lipid-TCR interaction, showing antigen deglycosylation generates the recognized phosphomycoketide neoepitope.\",\n      \"evidence\": \"CD1c tetramers, cell-free antigen-processing systems, and ex vivo human T cell detection\",\n      \"pmids\": [\"23530121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of host deglycosylating enzyme not established\", \"Generality of processing across CD1c antigens unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CD1c+ myeloid DCs as a functionally specialized subset that cross-primes CD8 T cells and polarizes T-helper responses through distinctive, often IL-12-independent, cytokine programs.\",\n      \"evidence\": \"Purified blood/tissue DC subset functional assays, TLR stimulation, cross-presentation and priming assays, IL-12 neutralization and an IL-12-deficient patient\",\n      \"pmids\": [\"23794066\", \"23562160\", \"25765676\", \"22678905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between CD1c lipid presentation and these DC effector functions unclear\", \"Molecular basis of subset-specific cytokine wiring incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CD1c antigen repertoire to a tumor-associated self lipid (methyl-lysophosphatidic acid), demonstrating CD1c-restricted T cells can recognize and kill CD1c+ leukemia in vitro and in vivo.\",\n      \"evidence\": \"Lipid biochemistry, CD1c-blocked cytotoxicity, and xenograft mouse model\",\n      \"pmids\": [\"24935257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mLPA accumulation in leukemia not defined\", \"Therapeutic translatability untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved the structural basis of CD1c antigen presentation, mapping the A' pocket binding of the mycoketide chain and identifying diverse alpha1/alpha2 helix residues used by structurally varied TCRs.\",\n      \"evidence\": \"X-ray crystallography of CD1c-PM, surface plasmon resonance across multiple TCRs, and CD1c/TCR mutagenesis\",\n      \"pmids\": [\"25298532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No single archetypical TCR footprint—rules of recognition incomplete\", \"Self-lipid complexes not crystallized here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CD1c serves Vdelta1+ gammadelta TCRs directly and discriminates permissive from non-permissive lipid ligands, broadening CD1c's role across T cell lineages.\",\n      \"evidence\": \"CD1c tetramer staining with Vdelta selection and Vdelta1 domain mutagenesis across diverse lipids\",\n      \"pmids\": [\"26755823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological gammadelta ligand in vivo unidentified\", \"Structural basis of gammadelta-CD1c contact not solved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked CD1c conformation to autoreactivity, showing self-lipid occupancy (cholesteryl esters, acylated steryl glycosides) stabilizes conformations forming a footprint for self-reactive TCRs.\",\n      \"evidence\": \"2.4 Å crystal structure, molecular dynamics, lipid loading, and TCR binding assays\",\n      \"pmids\": [\"26884207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological abundance of these self-lipids on APCs unclear\", \"Consequences of autoreactivity in vivo not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural mechanism of CD1c TCR polyspecificity, showing TCRs dock over the closed portal without contacting fully sequestered small self lipids—explaining lipid-permissive autoreactivity.\",\n      \"evidence\": \"CD1c tetramer staining with diverse self lipids and crystallography of a TCR-CD1c complex\",\n      \"pmids\": [\"29531339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional threshold separating tolerance from autoreactivity unknown\", \"Role of portal sequestration for larger antigens unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced the antigen-processing model by showing hydrolysis-resistant phosphomycoketide analogs bind CD1c normally but are recognized differently by T cells, indicating glycolipid hydrolysis during presentation.\",\n      \"evidence\": \"Synthetic analogs, crystallography of CD1c-analog complexes, and T cell assays\",\n      \"pmids\": [\"34536421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and localization of the responsible hydrolase still unknown\", \"Kinetics of processing during presentation undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified post-transcriptional control of CD1c expression by miR-381-3p as part of an IL-10-driven immunosuppressive circuit during mycobacterial infection.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter, miR-381-3p inhibition in BCG-infected DCs, and TB patient DC analysis\",\n      \"pmids\": [\"27296666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo causal role of the circuit not established\", \"Other regulators of CD1c expression not surveyed here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD1c lipid surveillance, conformational autoreactivity, and the effector functions of CD1c+ DCs are mechanistically integrated in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified host enzyme performing antigen deglycosylation\", \"Connection between CD1c lipid presentation and CD1c+ DC cytokine programs unestablished\", \"In vivo significance of ILT4-sink and autoreactivity not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 10, 11, 12, 22, 27]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [16, 23, 26, 28]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [4, 16, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 16, 17, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"B2M\", \"ILT4\", \"TRAV/TRBV TCR\", \"TRDV1 (Vdelta1 TCR)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}