Affinage

CD1D

Antigen-presenting glycoprotein CD1d · UniProt P15813

Length
335 aa
Mass
37.7 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD1d is a non-polymorphic MHC class I-like antigen-presenting molecule that loads lipid and glycolipid antigens and displays them at the cell surface to NKT cells, governing innate-like T cell immunity at barrier and lymphoid sites (PMID:17581592, PMID:10523605). Maturation and trafficking of CD1d depend on β2-microglobulin, which is required for Golgi transit and acquisition of endoglycosidase-H-resistant mature glycosylation (PMID:10092605). Antigen loading is orchestrated in the ER by microsomal triglyceride transfer protein (MTP), which associates with CD1d and directly transfers phospholipids onto nascent molecules, a step required for presentation of both exogenous α-galactosylceramide and endogenous lipids (PMID:15107843, PMID:16087713). The CD1d groove accommodates a broad spectrum of lipids — glycosphingolipids, phosphatidylinositol, cardiolipin, lysophosphatidylcholine, sphingomyelin, and dietary α-linked monohexosylceramides — with the presented species and its conformation dictating recognition outcomes (PMID:10523605, PMID:21376640, PMID:21389252, PMID:22395072, PMID:31636468, PMID:28716901). Structural studies establish that type I (invariant) NKT TCRs dock parallel at the extreme end of the cleft via conserved germline-encoded α-chain contacts, while autoreactivity is conferred by a hydrophobic CDR3β motif; γδ and atypical/type II NKT TCRs instead engage CD1d orthogonally over the A' or F' pockets, defining a repertoire of distinct docking strategies (PMID:17581592, PMID:24076636, PMID:21376640, PMID:26875526, PMID:31748533). Beyond antigen display, the CD1d cytoplasmic tail transduces intrinsic signals: tail tyrosine phosphorylation recruits JAK2 to activate STAT3 and anti-apoptotic effectors protecting hepatocytes, epithelial CD1d engagement drives a protective STAT3→IL-10 axis whose loss causes NKT-mediated colitis, and in enterochromaffin cells CD1d ligation activates Pyk2 to trigger serotonin secretion (PMID:24717441, PMID:38438948, PMID:37354904). CD1d surface levels are controlled transcriptionally and post-transcriptionally by retinoic acid/RARα and PPARγ, IFN-γ, miR-155/Ets-1, and HDAC2, and post-translationally by ER stress and ubiquitin-dependent endocytosis, the latter exploited by KSHV MIR proteins and HIV-1 Nef to evade NKT surveillance (PMID:15864354, PMID:15916790, PMID:16982809, PMID:8760056, PMID:24717441, PMID:25929465, PMID:27614429).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1996 Medium

    Established that CD1d expression is inducible, showing IFN-γ drives CD1d mRNA and surface protein on intestinal epithelium and linking the molecule to inflammatory regulation.

    Evidence Whole-cell ELISA and RT-PCR across epithelial cell lines with cytokine specificity controls

    PMID:8760056

    Open questions at the time
    • Did not identify the transcription factors mediating induction
    • No NKT functional readout linked to the increased expression
  2. 1999 High

    Defined the biosynthetic and localization requirements of CD1d, showing β2m association is required for Golgi transit and mature glycosylation while β2m-independent immature forms reach the surface, particularly apically in epithelium.

    Evidence Pulse-chase metabolic labeling, endo-H/N-glycanase digestion, surface biotinylation, and confocal microscopy in transfected and epithelial cells

    PMID:10092605 PMID:10221650

    Open questions at the time
    • Functional consequence of the β2m-independent apical form for antigen presentation unresolved
    • Did not address lipid loading along this trafficking route
  3. 1999 High

    Provided the first quantitative biophysical proof that CD1d directly binds glycolipid antigen, establishing it as a lipid-binding presentation molecule with broad ligand capacity.

    Evidence Surface plasmon resonance and plate-bound presentation assays with purified recombinant soluble CD1d

    PMID:10523605

    Open questions at the time
    • Did not resolve the structural basis of TCR engagement
    • Loading mechanism in cells not addressed
  4. 2001 Medium

    Enabled direct detection of antigen-specific NKT cells by reconstituting functional CD1d-glycolipid tetramers, providing a tool that anchored subsequent functional and clinical studies.

    Evidence Oxidative refolding chromatography of denatured CD1d/β2m with synthetic lipids and ex vivo tetramer staining

    PMID:11248072

    Open questions at the time
    • Methodological advance rather than mechanistic insight into CD1d biology
    • Single laboratory
  5. 2005 High

    Identified the ER chaperone that loads CD1d, showing MTP associates with CD1d and directly transfers phospholipids onto it, a step required in vivo for NKT activation.

    Evidence Reciprocal Co-IP, hepatocyte-specific Mttp knockout, siRNA, and in vitro lipid transfer with purified MTP and recombinant CD1d

    PMID:15107843 PMID:16087713

    Open questions at the time
    • How MTP-loaded endogenous lipids are exchanged for antigenic lipids in endosomes not defined
    • Selectivity for phospholipids over other ER lipids incompletely mapped
  6. 2005 Medium

    Revealed the CD1d cytoplasmic tail as a target of pathogen immune evasion, with KSHV MIR proteins ubiquitinating a tail lysine to trigger endocytosis and HIV-1 Nef binding the tail to downregulate surface CD1d.

    Evidence Ubiquitination and endocytosis assays, Co-IP, and cytoplasmic tail mutant/deletion constructs with NKT activation readouts

    PMID:15864354 PMID:15916790

    Open questions at the time
    • Nef interaction shown in a single laboratory without reciprocal validation in infection
    • Endogenous host machinery that normally uses this endocytosis signal not fully identified
  7. 2006 Medium

    Established retinoic acid signaling as a direct transcriptional control of CD1d, with PPARγ acting upstream through ATRA synthesis and RARα directly driving CD1d expression in dendritic cells and B cells.

    Evidence Pharmacological PPARγ/RARα modulation, enzyme assays, and iNKT co-culture in human DCs and B cells

    PMID:16982809 PMID:21451111

    Open questions at the time
    • Direct RARα occupancy of the CD1D promoter not shown structurally
    • Single laboratory for each cell type
  8. 2007 High

    Resolved the molecular docking mode of the canonical NKT TCR, showing parallel binding at the cleft end with conserved germline α-chain contacts to the CD1d-antigen complex.

    Evidence X-ray crystallography of the NKT TCR–CD1d–α-GalCer ternary complex

    PMID:17581592

    Open questions at the time
    • Did not explain recognition of self versus foreign lipids
    • Limited to a single TCR/antigen pair
  9. 2007 Medium

    Linked organelle stress to CD1d function, showing ER stress in steatotic hepatocytes impairs CD1d trafficking and depletes liver NKT cells despite normal mRNA.

    Evidence Subcellular fractionation, surface flow cytometry, and T cell activation in ob/ob and tunicamycin-treated mice

    PMID:17607300

    Open questions at the time
    • Molecular checkpoint coupling the UPR to CD1d export not identified
    • Single laboratory
  10. 2011 High

    Explained the structural basis of NKT autoreactivity and broadened the lipidome CD1d can present, showing a CDR3β hydrophobic motif drives self-recognition and that cardiolipin loading stimulates γδ T cells.

    Evidence High-resolution crystal structures of NKT TCR–PI–CD1d and CD1d–cardiolipin complexes with functional T cell assays

    PMID:21376640 PMID:21389252

    Open questions at the time
    • Physiological abundance of these self-lipids on CD1d not quantified
    • γδ recognition of cardiolipin structurally inferred rather than co-crystallized
  11. 2012 High

    Demonstrated antigen-induced conformational plasticity of CD1d, with lysophosphatidylcholine opening the A' pocket and TCR binding enforcing headgroup displacement and a closed conformation.

    Evidence Crystal structures of CD1d–LPC and the iNKT TCR ternary complex with functional iNKT assays

    PMID:22395072

    Open questions at the time
    • Generality of induced-fit recognition across other lysolipids not established
    • Single antigen-TCR pair
  12. 2013 High

    Expanded the CD1d-restricted TCR universe, showing a Vδ1 γδ TCR docks orthogonally over the A' pocket using germline CDR1δ, distinct from invariant NKT recognition.

    Evidence X-ray crystallography of a γδ TCR–CD1d–α-GalCer complex with primary γδ T cell functional assays

    PMID:24076636

    Open questions at the time
    • In vivo antigens driving γδ recognition of CD1d not defined
    • Single TCR studied
  13. 2013 Medium

    Identified a co-receptor partnership for epithelial CD1d, showing CEACAM5 binds CD1d via its B3 domain and bridges CD8α to activate Lck and CD8+ suppressor T cells.

    Evidence Domain-mapped Co-IP, deglycosylation mutants, and Lck activation/suppression assays in intestinal epithelium

    PMID:24104458

    Open questions at the time
    • Single laboratory without reciprocal in vivo validation
    • Lipid antigen requirement for this CD8+ T cell activation unclear
  14. 2014 High

    Established intrinsic epithelial CD1d signaling as protective, defining a CD1d→STAT3→IL-10/HSP110 axis whose loss causes NKT-mediated colitis.

    Evidence IEC-specific conditional deletion of CD1d, MTP, IL-10, and HSP110 with STAT3 assays, colitis models, and bone marrow chimeras

    PMID:24717441

    Open questions at the time
    • Upstream ligand triggering epithelial CD1d signaling in vivo not defined
    • Connection to the tail tyrosine signaling described later not yet integrated
  15. 2015 Medium

    Defined post-transcriptional and transcriptional repression of CD1d on B cells, with TLR9-induced miR-155 targeting the CD1D 3'-UTR and Ets-1 directly regulating transcription, with relevance to SLE.

    Evidence 3'-UTR luciferase reporters, miR-155 gain/loss, Ets-1 binding analysis, and iNKT activation assays

    PMID:25929465

    Open questions at the time
    • Relative contributions of miR-155 versus Ets-1 in vivo not quantified
    • Single laboratory
  16. 2016 Medium

    Identified chromatin-level control of CD1d, showing HDAC2 occupies the CD1D promoter and represses expression, with HDAC inhibition enhancing NKT responses against lymphoma.

    Evidence ChIP at the CD1D promoter, HDAC2 siRNA, and NKT activation/HDAC inhibitor assays

    PMID:27614429

    Open questions at the time
    • Histone marks and co-repressors at the locus not mapped
    • Single laboratory
  17. 2016 High

    Showed that diverse NKT TCR repertoire usage manifests as varied docking geometries, with atypical NKT TCRs engaging CD1d orthogonally over the A' pocket.

    Evidence Crystal structures of multiple atypical NKT TCR–CD1d–α-GalCer complexes with antigen reactivity assays

    PMID:26875526

    Open questions at the time
    • Functional significance of docking diversity for in vivo selection not resolved
    • Limited number of TCRs sampled
  18. 2017 High

    Linked hepatocyte CD1d to liver iNKT homeostasis, showing hepatocyte-specific loss of MTP or CD1d increases liver iNKT numbers through altered iNKT apoptosis, and biochemically captured a dietary α-anomeric antigen at the CD1d–TCR interface.

    Evidence Conditional hepatocyte MTP/CD1d knockouts with apoptosis/hepatitis models, and TCR-trap capture with mass spectrometry of milk monohexosylceramides

    PMID:28716901 PMID:28893990

    Open questions at the time
    • Mechanism by which hepatocyte CD1d controls iNKT apoptosis not molecularly defined
    • Antigen capture from a single laboratory
  19. 2018 Medium

    Demonstrated a regulatory immune function for B cell CD1d, showing Breg CD1d-lipid presentation drives iNKT IFN-γ to dampen Th1/Th17 responses and ameliorate arthritis.

    Evidence B cell-conditional CD1d knockout, chimeras, adoptive transfer, and experimental arthritis with cytokine/metabolic assays

    PMID:29449556

    Open questions at the time
    • Endogenous lipid antigen presented by Bregs not identified
    • Single laboratory
  20. 2019 High

    Identified sphingomyelin as a non-activating CD1d ligand whose accumulation impairs antigen presentation, linking acid sphingomyelinase to thymic iNKT selection, and structurally diversified type II NKT recognition via an F'-pocket docking mode.

    Evidence ASM-deficient mouse/human (Niemann-Pick) studies with pharmacological rescue, plus crystallography of a type II NKT TCR–CD1d–α-GlcADAG complex

    PMID:31636468 PMID:31748533

    Open questions at the time
    • How sphingomyelin is normally turned over to permit antigen loading in vivo incompletely defined
    • Breadth of type II recognition modes not exhausted
  21. 2022 Medium

    Uncovered a metabolic regulatory role for CD1d in macrophages, controlling CD36 internalization to limit lipid import and restrain TLR-driven cytokine secretion.

    Evidence CD1d-KO macrophage transcriptomics/metabolomics, CD36 internalization assays, and pharmacological CD36 blockade rescue

    PMID:36344546

    Open questions at the time
    • Molecular link between CD1d and CD36 trafficking not defined
    • Single laboratory
  22. 2023 Medium

    Defined intrinsic CD1d tail signaling pathways, showing tail tyrosine phosphorylation recruits JAK2 to activate STAT3 anti-apoptotic signaling in hepatocytes, and CD1d ligation activates Pyk2 to drive serotonin secretion from enterochromaffin cells.

    Evidence Hepatocyte CD1d gain/loss with crosslinking and JAK2/STAT3 assays in lipotoxicity/liver injury models; iNKT–EC co-culture with Pyk2 inhibition, calcium imaging, and germ-free mice

    PMID:37354904 PMID:38438948

    Open questions at the time
    • Physiological ligand triggering hepatocyte CD1d phosphorylation not identified
    • Both mechanisms from single laboratories
  23. 2024 Medium

    Extended CD1d ligand recognition to synthetic lipids, showing ionizable lipid amine headgroups in nanoparticles bind CD1d and promote lipid-raft-driven immunogenicity that suppresses anti-PEG IgM.

    Evidence Direct binding assays, lipid raft and cytokine measurements, and structure-activity analysis of ionizable lipid headgroups

    PMID:39363106

    Open questions at the time
    • Structural mode of ionizable lipid binding to CD1d not resolved
    • Single laboratory

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct CD1d cytoplasmic-tail signaling modules (ubiquitin-dependent endocytosis, JAK2-STAT3, Pyk2) are integrated, what physiological ligands trigger them, and how lipid loading is coordinated across ER and endosomal compartments remain unresolved.
  • No unified model linking tail tyrosine phosphorylation events to downstream effectors across cell types
  • Endogenous physiological triggers of CD1d intrinsic signaling unknown
  • In vivo lipid exchange machinery downstream of MTP not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 8 GO:0060089 molecular transducer activity 4 GO:0140110 transcription regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 1
Partners
B2MCEACAM5JAK2MIR2MTTPNEF

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Crystal structure of human NKT TCR complexed with CD1d bound to α-galactosylceramide revealed that the NKT TCR docks parallel to, and at the extreme end of, the CD1d-binding cleft in a lock-and-key interaction with the lipid antigen, with the conserved TCR α-chain making primary contacts with the CD1d-antigen complex. X-ray crystallography of NKT TCR–CD1d–α-GalCer ternary complex Nature High 17581592
2013 A human Vδ1+ γδ TCR binds CD1d–α-GalCer orthogonally over the A' pocket of CD1d, with the Vδ1-chain and germline-encoded CDR1δ loop dominating CD1d contacts, while the CDR3γ loop determines α-GalCer specificity—a docking mode distinct from type I NKT TCRs. X-ray crystallography of γδ TCR–CD1d–α-GalCer complex; functional assays with primary γδ T cells Nature immunology High 24076636
2004 Microsomal triglyceride transfer protein (MTP), residing in the endoplasmic reticulum, associates with CD1d in hepatocytes and is required for CD1d-mediated glycolipid antigen presentation; conditional deletion of Mttp in hepatocytes redistributes CD1d expression and abolishes invariant NKT cell activation. Co-immunoprecipitation, conditional hepatocyte-specific Mttp knockout mice, siRNA silencing in intestinal epithelial cells, in vivo NKT activation assays Nature medicine High 15107843
2005 MTP directly transfers phospholipids (but not triglycerides) onto recombinant CD1d in vitro, functioning as an ER chaperone that loads endogenous lipids onto nascent CD1d; chemical inhibition of MTP lipid transfer reduces CD1d-mediated presentation of α-GalCer and endogenous antigens in dendritic cells. In vitro lipid transfer assay with purified MTP and recombinant CD1d; pharmacological MTP inhibition; siRNA knockdown; MHC class II presentation control The Journal of experimental medicine High 16087713
1999 Soluble mouse and human CD1d molecules bind α-galactosylceramide at neutral pH as measured by surface plasmon resonance; CD1d can also bind non-antigenic β-GalCer and phosphatidylethanolamine, indicating broad lipid-binding capacity. The orientation of the galactose head group is more critical for TCR contact than for CD1d binding. Surface plasmon resonance binding assay, in vitro antigen presentation with plate-bound soluble CD1d, purified recombinant CD1d proteins The Journal of experimental medicine High 10523605
2011 Crystal structure (2.3 Å) of an autoreactive NKT TCR–phosphatidylinositol–CD1d complex revealed that NKT TCR autoreactivity is mediated by a hydrophobic motif in the non-germline-encoded CDR3β loop that promotes self-association with CD1d, while germline-encoded recognition of CD1d is conserved between self- and foreign antigen recognition. X-ray crystallography; NKT cell functional assays with natural self-antigen-loaded CD1d Immunity High 21376640
2011 CD1d binds cardiolipin (a tetra-acylated phospholipid) with two alkyl chains buried in the binding groove and two exposed to solvent, as revealed by a 2.3 Å crystal structure of murine CD1d–cardiolipin; this complex stimulates splenic and hepatic γδ T cells to proliferate and secrete IFN-γ and RANTES in a CD1d-restricted manner. X-ray crystallography of murine CD1d–cardiolipin complex; lipid loading experiments; in vitro and in vivo γδ T cell stimulation assays Journal of immunology High 21389252
2012 Human CD1d presenting lysophosphatidylcholine adopts an altered conformation with a shifted α1 helix and open A' pocket compared to glycolipid-loaded CD1d; iNKT TCR binding requires a 7-Å displacement of the LPC headgroup but stabilizes a closed CD1d-LPC conformation, with CDR3α anchoring the TCR footprint. X-ray crystallography of CD1d–LPC and iNKT TCR–CD1d–LPC complexes; functional iNKT cell assays The EMBO journal High 22395072
2005 KSHV MIR proteins (MIR1 and MIR2) downregulate CD1d surface expression by ubiquitinating a unique lysine residue in the CD1d α-chain cytoplasmic tail, triggering endocytosis without accelerated lysosomal degradation, resulting in reduced activation of CD1d-restricted T cells. Transfection of MIR proteins into uninfected cells; ubiquitination assays; endocytosis assays; T cell activation assays; cytoplasmic tail mutant CD1d constructs The Journal of clinical investigation High 15864354
2005 HIV-1 Nef physically interacts with the cytoplasmic tail of CD1d (requiring the last 6–10 amino acids), reducing CD1d cell surface expression and impairing CD1d-restricted NKT cell activation; tail-deleted CD1d mutants are resistant to Nef-mediated downregulation. Co-immunoprecipitation of Nef and CD1d; flow cytometry of surface CD1d; cytoplasmic tail deletion mutants; NKT cell activation assay Virology Medium 15916790
2006 PPARγ indirectly upregulates CD1d expression in human dendritic cells by inducing retinol/retinal metabolizing enzymes (RDH10 and RALDH2), increasing intracellular all-trans retinoic acid (ATRA) synthesis; ATRA then activates RARα, which directly drives CD1d transcription and enhanced iNKT cell activation. Gene expression analysis; pharmacological PPARγ activation; enzyme activity assays; RARα pathway dissection; iNKT cell co-culture activation assays The Journal of experimental medicine Medium 16982809
1999 In the absence of β2-microglobulin (β2m), CD1d is expressed on the cell surface as an endoglycosidase-H-sensitive 45 kDa glycoprotein with immature glycosylation, whereas in the presence of β2m, CD1d acquires endoglycosidase-H resistance (48 kDa mature form); β2m association is required for CD1d to transit through the Golgi and acquire mature glycosylation. Pulse-chase metabolic labeling; endoglycosidase-H and N-glycanase digestion; transfected cell lines with and without β2m; Western blotting The Journal of biological chemistry High 10092605
1999 CD1d is localized to the apical and lateral surfaces of intestinal epithelial cells, with a large apical intracellular pool; both β2m-associated (48–50 kDa) and non-glycosylated β2m-independent (37 kDa) forms are present, with the 37 kDa form specifically on the apical surface. Confocal laser microscopy; selective apical/basolateral biotin labeling followed by immunoprecipitation; N-glycanase digestion; Western blotting International immunology Medium 10221650
1996 IFN-γ upregulates CD1d mRNA and cell surface protein expression on intestinal epithelial cell lines in a dose- and time-dependent, cytokine-specific manner. Whole-cell ELISA for surface CD1d; RT-PCR for CD1d mRNA; cytokine-specific controls across multiple epithelial cell lines The American journal of physiology Medium 8760056
2003 Intestinal lumenal heat shock protein 110 (Hsp110) acts as an autocrine regulator of CD1d surface expression on intestinal epithelial cells, inducing CD1d expression at mRNA and protein levels. RT-PCR; confocal microscopy; cell surface ELISA; Western blot; biochemical fractionation and identification of Hsp110 from lumenal contents; immunolocalization in vivo The Journal of clinical investigation Medium 12952923
2008 KSHV lytic replication downregulates CD1d surface expression; viral danger signals (type I IFN, TLR ligands, viruses) selectively increase CD1D mRNA and surface CD1d on human myeloid dendritic cells while decreasing CD1A, CD1B, and CD1E, leading to NKT cell activation with a Th1-like response. Flow cytometry of CD1d surface expression; RT-PCR quantification of CD1 family mRNAs; NKT cell co-culture activation assays; type I IFN pathway analysis European journal of immunology Medium 18253929
2014 Engagement of epithelial CD1d activates STAT3 signaling and drives STAT3-dependent transcription of IL-10, HSP110, and CD1d itself in intestinal epithelial cells; IEC-specific deletion of CD1d (or its regulator MTP) causes severe NKT-cell-mediated colitis, defining a protective epithelial CD1d→STAT3→IL-10 axis. Conditional IEC-specific gene deletion (CD1d, MTP, IL-10, HSP110); STAT3 activation assays; in vivo colitis models; bone marrow chimeras Nature High 24717441
2007 Endoplasmic reticulum stress in steatotic hepatocytes reduces CD1d protein trafficking to the plasma membrane (despite normal CD1d mRNA levels), impairing CD1d-restricted T cell activation and depleting liver NKT cells; tunicamycin-induced ER stress recapitulates these effects in lean mice. Subcellular fractionation and flow cytometry for surface CD1d; CD1d-restricted T cell activation assays; ob/ob and tunicamycin-treated mouse models Laboratory investigation Medium 17607300
2017 Hepatocyte-specific loss of MTP causes defective CD1d function and increases liver iNKT cell numbers due to altered iNKT cell apoptosis; hepatocyte-specific CD1d deletion produces the same phenotype, demonstrating that hepatocyte CD1d controls liver iNKT cell homeostasis. Conditional hepatocyte-specific MTP and CD1d knockout mice; flow cytometry; apoptosis assays; iNKT-cell-mediated hepatitis model Proceedings of the National Academy of Sciences High 28893990
2023 CD1d crosslinking on hepatocytes induces tyrosine phosphorylation of the CD1d cytoplasmic tail, recruiting and activating JAK2, which then phosphorylates STAT3 to upregulate anti-apoptotic effectors (Bcl-xL, Mcl-1) and reduce cleaved caspase 3/7, protecting hepatocytes from apoptosis independently of NKT cell interactions. Hepatocyte-specific CD1d overexpression and knockdown; anti-CD1d crosslinking; JAK2 phosphorylation and STAT3 activation assays; in vitro palmitic acid lipotoxicity model; in vivo liver injury models (HFD, MCD diet, Fas agonist, ConA) Journal of hepatology Medium 38438948
2008 Anti-CD1d monoclonal antibody engagement of CD1d on myeloma cells induces caspase-independent cell death associated with Bax overexpression and mitochondrial membrane potential loss; this requires the CD1d cytoplasmic tail but not the tyrosine residue critical for lysosomal sorting. Anti-CD1d mAb crosslinking; apoptosis/cell death assays; cytoplasmic tail deletion/mutation constructs; Bax expression analysis; mitochondrial membrane potential measurement Blood Medium 19056691
2001 CD1d-glycolipid tetramers generated by oxidative refolding chromatography of fully denatured human CD1d and β2m in the presence of synthetic lipids are functional and specific for iNKT cells, enabling ex vivo identification and enumeration of NKT cells in clinical samples. Oxidative refolding chromatography; tetramer construction; ex vivo flow cytometry staining of peripheral blood and intrahepatic T cells Proceedings of the National Academy of Sciences Medium 11248072
2019 Sphingomyelin occupies the CD1d binding groove as a non-activating endogenous lipid; absence of acid sphingomyelinase (ASM) in mice leads to sphingomyelin accumulation, diminished CD1d-restricted antigen presentation, impaired iNKT cell selection in the thymus, and decreased iNKT cell levels; pharmacological ASM administration restores antigen presentation and iNKT cell levels. ASM-deficient mouse and human (Niemann-Pick disease) studies; CD1d antigen presentation assays; thymic iNKT selection analysis; pharmacological ASM administration Nature immunology High 31636468
2006 Retinoic acid receptor α (RARα) signaling directly regulates CD1d expression in human B cells; CD40L activation downregulates CD1d by reducing RARα response gene expression, and RARα agonists reverse this downregulation; BCR activation upregulates CD1c independently of RAR signaling. Flow cytometry; RARα agonist treatment; B cell activation with CD40L and BCR crosslinking; functional NKT cell cytotoxicity assay Journal of immunology Medium 21451111
2015 TLR9 activation induces miR-155, which directly targets the 3'-UTR of CD1D mRNA to reduce CD1d expression on B cells; the transcription factor Ets-1 also directly regulates CD1D gene transcription; these mechanisms collectively impair B cell antigen presentation to iNKT cells in SLE. miRNA target site reporter assays (3'-UTR luciferase); miR-155 overexpression/inhibition; Ets-1 transcription factor binding analysis; flow cytometry; iNKT cell activation assay European journal of immunology Medium 25929465
2016 HDAC2 binds to the CD1D promoter; knockdown of HDAC2 increases CD1d mRNA and surface expression, enhancing CD1d-mediated NKT cell antigen presentation; HDAC inhibitors enhance CD1d expression and NKT cell responses to lymphoma partially by relieving HDAC2-mediated repression of CD1D. ChIP of HDAC2 at CD1D promoter; HDAC2 siRNA knockdown; RT-PCR and flow cytometry for CD1d; NKT cell activation assays; HDAC inhibitor treatment Cancer immunology, immunotherapy Medium 27614429
2022 CD1d controls the internalization of the lipid transporter CD36 in macrophages; CD1d-deficient macrophages show downregulation of lipid metabolic pathways and increased exogenous lipid import via CD36, priming macrophages for enhanced TLR-stimulated cytokine secretion; blocking CD36-mediated lipid uptake restores normal metabolic and immune responses in CD1d-KO macrophages. CD1d-KO macrophage transcriptomics/metabolomics; CD36 internalization assays; pharmacological CD36 blockade; TLR stimulation cytokine assays Nature communications Medium 36344546
2023 CD1d ligation on intestinal enterochromaffin (EC) cells activates protein tyrosine kinase Pyk2, which restrains potassium conductance, leading to calcium influx and peripheral serotonin (5-HT) secretion; inhibitory sphingolipids from Bacteroides fragilis repress this 5-HT release via the same CD1d pathway. iNKT cell–EC cell co-culture; CD1d-blocking antibodies; Pyk2 inhibition; calcium imaging; potassium channel assays; germ-free mouse experiments Immunity Medium 37354904
2013 CEACAM5 physically interacts with CD1d through its B3 domain on intestinal epithelial cells; this interaction, together with CEACAM5–CD8α binding (requiring the N domain and its glycosylation), activates CD8-associated Lck and enables CD1d-mediated activation of CD8+ suppressor T cells. Co-immunoprecipitation; domain deletion mutants; N-domain deglycosylation; Lck activation assay; CD8+ T cell suppression assay Mucosal immunology Medium 24104458
2016 Atypical NKT TCRs (TRAV21-TRAJ8-TRBV7-8 and TRAV12-3-TRAJ27-TRBV6-5) dock orthogonally over the A'-pocket of CD1d in a mode distinct from all type I NKT TCR–CD1d complexes, showing that diverse NKT TCR repertoire usage manifests in varied docking strategies and antigen specificities toward CD1d–α-GalCer. X-ray crystallography of atypical NKT TCR–CD1d–α-GalCer complexes; functional antigen reactivity assays Nature communications High 26875526
2019 Type II NKT TCR directed against the microbial antigen α-glucuronosyl-diacylglycerol (α-GlcADAG) adopts an F'-pocket docking mode on CD1d, contrasting sharply with the A'-roof positioning of sulfatide-reactive type II NKT TCRs, demonstrating that diverse type II NKT TCRs use multiple distinct recognition strategies on CD1d. X-ray crystallography of type II NKT TCR–CD1d–α-GlcADAG complex; functional antigen reactivity assays Nature communications High 31748533
2017 A TCR trap method capturing lipid antigens at the CD1d–TCR interface identified α-linked monohexosylceramides from cow's milk as endogenous iNKT cell antigens, directly biochemically proving α-anomeric lipid antigens from a common dietary source occupy the CD1d–TCR interface. CD1d-lipid-TCR complex capture (TCR trap); mass spectrometry fragmentation distinguishing α- from β-anomeric monohexosylceramides Proceedings of the National Academy of Sciences Medium 28716901
2018 CD1d-lipid presentation by regulatory B cells (Bregs) drives iNKT cells to secrete IFN-γ, which contributes to downregulation of Th1 and Th17 responses and amelioration of experimental arthritis; mice lacking CD1d-expressing B cells fail to respond to α-GalCer treatment, and loss of B cell CD1d alters iNKT cell metabolic and cytokine regulation. Chimeric mice; B cell depletion and adoptive cell transfer; CD1d-conditional B cell-specific knockout; experimental arthritis model; cytokine and metabolic assays Nature communications Medium 29449556
2024 Amine headgroups of ionizable lipids in lipid nanoparticles directly bind to CD1d (and TLR4) and promote lipid-raft formation, driving LNP immunogenicity; these inflammatory signals inhibit anti-PEG IgM production, preventing loss of LNP efficacy on repeated dosing. Direct binding assays (CD1d and TLR4); lipid raft formation assays; immunoglobulin isotype profiling; cytokine measurement; structure-activity analysis of ionizable lipid headgroups Nature biomedical engineering Medium 39363106

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 482 17581592
2012 Recognition of CD1d-restricted antigens by natural killer T cells. Nature reviews. Immunology 370 23154222
2008 CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Current opinion in immunology 341 18501573
2013 CD1d-lipid antigen recognition by the γδ TCR. Nature immunology 271 24076636
1999 Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. Journal of immunology (Baltimore, Md. : 1950) 239 10352254
2003 CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. Journal of immunology (Baltimore, Md. : 1950) 184 12928408
2014 Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 174 24717441
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2007 Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers. Laboratory investigation; a journal of technical methods and pathology 79 17607300
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2006 Structure and binding kinetics of three different human CD1d-alpha-galactosylceramide-specific T cell receptors. The Journal of experimental medicine 76 16520393
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