Affinage

KLRD1

Natural killer cells antigen CD94 · UniProt Q13241

Length
179 aa
Mass
20.5 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLRD1 (CD94) is the invariant subunit of a family of heterodimeric NK- and T-cell receptors that survey cells for the non-classical MHC class I molecule HLA-E (mouse Qa-1b), thereby coupling detection of overall MHC class I integrity to control of cytotoxic effector function (PMID:8943374, PMID:9486650, PMID:9815261). CD94 is a C-type-lectin-fold glycoprotein whose structure is atypical — the second alpha-helix is replaced by a loop, the carbohydrate-binding site is altered, and the Ca2+ site is nonfunctional — and it assembles as a disulfide-linked dimer that pairs with NKG2 chains (PMID:10023772, PMID:9472066). Disulfide-bonded heterodimers with NKG2A/B form inhibitory receptors carrying cytoplasmic ITIMs, whereas pairing with NKG2C/E generates activating receptors that lack ITIMs and instead associate noncovalently with the ITAM-bearing adaptor DAP12 through complementary transmembrane charged residues (PMID:8943374, PMID:9045931, PMID:9655483, PMID:9485212). Crystal structures of CD94 alone, the CD94–NKG2A heterodimer, and the ternary CD94–NKG2A–HLA-E complex establish that the invariant CD94 chain dominates contact with HLA-E and its bound leader peptide in a lock-and-key mode, while the variable NKG2 chain lies peripheral; residues at the CD94–NKG2 interface (NKG2 167–170) account for the higher HLA-E affinity of the inhibitory CD94/NKG2A over the activating CD94/NKG2C (PMID:18083576, PMID:18332182, PMID:18448674). HLA-E recognition is strictly peptide-dependent, and subtle differences in the conformation of HLA class I leader peptides — only a subset of which are efficiently processed into functional epitopes — tune receptor engagement and the resulting NK response (PMID:10428963, PMID:18339401, PMID:37264229). Engagement of CD94/NKG2A by HLA-E triggers NKG2A ITIM tyrosine phosphorylation and SHP-1 recruitment, which blocks activation-receptor signaling (Syk/ZAP-70, Shc/Grb-2, ERK) and disrupts the actin network and lipid raft organization at the inhibitory immunological synapse, suppressing cytotoxicity (PMID:9565368, PMID:10358164, PMID:16951318). Through this inhibitory axis, CD94/NKG2A restrains NK and antigen-specific CD8+ T-cell cytotoxicity in viral infection and contributes, via the HLA-B→HLA-E→NKG2A education pathway, to healthy pregnancy (PMID:33887202, PMID:11812997, PMID:39121847), while CD94/NKG2E serves as an activating receptor required for resistance to ectromelia virus (PMID:21439856).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Establishing that CD94 is not a stand-alone receptor but the shared subunit of a family of heterodimers explained how a single invariant chain could give rise to both inhibitory and activating signaling.

    Evidence Co-immunoprecipitation, SDS-PAGE, and cytoplasmic-domain sequencing of CD94 paired with NKG2A/B/C/E, plus serological and functional discrimination of inhibitory vs stimulatory forms

    PMID:8943374 PMID:8955184

    Open questions at the time
    • Did not identify the ligand of the heterodimers
    • Did not define the structural basis of preferential heterodimer assembly
  2. 1997 High

    Assigning the inhibitory function to the NKG2A/B ITIMs and showing CD94 is required for NKG2A surface maturation defined the molecular logic of the inhibitory receptor.

    Evidence Co-immunoprecipitation with anti-CD94, glycosylation maturation analysis, and ITIM sequence analysis on NK clones

    PMID:9034158 PMID:9045931

    Open questions at the time
    • Did not identify the recruited phosphatase
    • Ligand still unknown
  3. 1996 High

    Demonstrating divergent intracellular signaling distinguished the two receptor classes functionally before their ligand was known.

    Evidence Kinase activation and phosphorylation assays on sorted activating vs inhibitory NK clones after CD94 ligation

    PMID:8816383

    Open questions at the time
    • Performed by antibody ligation rather than physiological ligand
    • Phosphatase identity not yet pinned
  4. 1998 High

    Identification of HLA-E (and mouse Qa-1b) as the ligand revealed that CD94/NKG2 receptors monitor global MHC class I status by reading leader-peptide-loaded non-classical class I.

    Evidence HLA-E and Qa-1b tetramer binding to transfectants and NK clones, leader-peptide loading, and antibody-blocked cytotoxicity assays

    PMID:9486650 PMID:9560253 PMID:9815261

    Open questions at the time
    • Did not quantify affinity differences between inhibitory and activating receptors
    • Atomic basis of recognition unresolved
  5. 1998 High

    Showing that the activating CD94/NKG2C complex requires DAP12 through transmembrane charged residues explained how the ITIM-less activating receptors deliver positive signals.

    Evidence Co-immunoprecipitation and transmembrane-domain mutagenesis with surface expression analysis; later extended to T cells

    PMID:15940674 PMID:9655483

    Open questions at the time
    • DAP12 downstream signaling steps for this receptor not fully traced
    • T-cell co-IP evidence single lab (Medium)
  6. 1998 High

    Linking HLA-E engagement to NKG2A phosphorylation and SHP-1 recruitment provided the proximal biochemical mechanism of inhibition.

    Evidence Tyrosine phosphorylation and SHP-1 co-immunoprecipitation in primary NK cells and RBL-2H3 reconstitution

    PMID:10570324 PMID:9565368

    Open questions at the time
    • Downstream substrates of SHP-1 not yet identified
    • Xenoreactive study (10570324) single lab, Medium confidence
  7. 1999 High

    Direct affinity measurement established that the inhibitory receptor binds HLA-E more strongly than the activating one, providing a kinetic basis for the dominance of inhibition.

    Evidence Surface plasmon resonance with soluble recombinant HLA-E and CD94/NKG2A vs CD94/NKG2C, correlated with NK functional assays

    PMID:10428963

    Open questions at the time
    • Structural origin of the affinity difference not yet localized
    • Single-lab kinetic measurement
  8. 1999 High

    Defining the downstream inhibitory cascade showed how SHP-1 recruitment translates into blocked effector activation.

    Evidence Kinase, co-IP, and ERK activation assays demonstrating block of Syk, CD16-zeta phosphorylation, and Shc/Grb-2 complex formation; CD69-triggered ERK suppression in RBL transfectants

    PMID:10358164 PMID:10671222

    Open questions at the time
    • Did not address synapse-level cytoskeletal effects
    • Reconstituted-system readouts
  9. 1999 High

    The first CD94 crystal structure revealed its atypical C-type lectin fold and a putative HLA-E binding surface, reframing CD94 as a lectin-like receptor that does not bind carbohydrate canonically.

    Evidence X-ray crystallography of the CD94 ectodomain at 2.6 Å

    PMID:10023772

    Open questions at the time
    • Structure of the heterodimer and the ligand complex not yet solved
    • Functional carbohydrate/Ca2+ sites inferred, not tested
  10. 2004 High

    Mutagenesis mapping showed inhibitory and activating receptors engage largely shared but partly distinct HLA-E surfaces, giving the first explanation for differential recognition.

    Evidence Alanine-scanning mutagenesis of HLA-E with binding to soluble CD94/NKG2A and CD94/NKG2C

    PMID:14971033

    Open questions at the time
    • Did not resolve which subunit contributes which contacts atomically
  11. 2008 High

    Structures of the heterodimer and the ternary CD94–NKG2A–HLA-E complex established that the invariant CD94 chain dominates ligand contact and that NKG2 interface residues, not direct HLA-E contacts, set affinity differences.

    Evidence X-ray crystallography of CD94–NKG2A (2.5 Å), the ternary complex, and HLA-E/peptide structures, with interface mutagenesis

    PMID:18083576 PMID:18332182 PMID:18339401 PMID:18448674

    Open questions at the time
    • Did not connect binding to dynamics of signaling at the synapse
  12. 2006 High

    Imaging the inhibitory synapse connected SHP-1 activity to physical disruption of the effector machinery, explaining how inhibition aborts killing.

    Evidence Confocal imaging, Vav1/ERM phosphorylation assays, and pharmacological actin and cholesterol perturbations at the inhibitory NK immunological synapse; earlier trafficking/recycling studies

    PMID:12444112 PMID:15607803 PMID:16951318

    Open questions at the time
    • Did not fully resolve order of actin disruption vs raft exclusion in vivo
    • Trafficking compartment identity partly defined
  13. 2011 High

    Loss-of-function mouse genetics established the physiological roles and limits of CD94, showing it is dispensable for development yet required for the activating CD94/NKG2E response to a poxvirus.

    Evidence CD94-deficient and naturally CD94-deficient (DBA/2J) mouse models with viral and bacterial challenge, NK development, and tolerance assays

    PMID:11782535 PMID:21151939 PMID:21439856

    Open questions at the time
    • Redundant inhibitory pathways masking phenotypes not fully mapped
    • Allelic expression regulation (Medium) needs mechanism
  14. 2002 High

    Inducible expression on CD8+ T cells demonstrated that the inhibitory receptor restrains antigen-specific CTL responses, extending CD94 biology beyond NK cells.

    Evidence In vivo polyoma virus infection with CD94/NKG2A blockade; IL-15- and TGF-β-driven induction of CD94/NKG2A on superantigen-stimulated T cells with functional blocking

    PMID:11812997 PMID:9448304 PMID:9933082

    Open questions at the time
    • Transcriptional control of induction defined only by cytokine inputs (Medium)
    • Consequences for tumor immunity not fully addressed here
  15. 2021 High

    Pregnancy and exhaustion models linked the HLA-E→NKG2A axis to NK-cell education in reproduction and to a LAG-3/TOX-dependent cytotoxic subset of exhausted T cells, broadening physiological context.

    Evidence NKG2A-targeted KO crossed to wild-type males with placental/fetal phenotyping plus human GWAS; LAG-3 deletion in chronic LCMV with single-cell, TOX, and Qa-1b functional analysis

    PMID:33887202 PMID:39121847

    Open questions at the time
    • Mechanism linking NK education to vascular outcomes not fully resolved
    • Human translation of exhaustion circuit inferred
  16. 2023 High

    Systematic analysis of leader-peptide variants showed that only a subset of HLA signal peptides are efficiently processed into functional CD94/NKG2 epitopes, and competition among them tunes receptor engagement.

    Evidence Quantitative HLA-E surface expression and CD94/NKG2A/C engagement assays across 16 common signal-peptide variants with competitive loading; HLA-G allotype binding by ligand capture/reciprocal recombinant assays

    PMID:32575403 PMID:37264229

    Open questions at the time
    • Population-level consequences of variant repertoire not addressed
    • HLA-G recognition single-lab (Medium)

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD94/NKG2 receptor surface levels, recycling, and ligand competition are integrated to set NK and T-cell activation thresholds in human disease and therapy remains incompletely defined.
  • No timeline evidence on regulation of receptor turnover during chronic human disease
  • Therapeutic modulation of the axis not characterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
DAP12HLA-EHSP70NKG2ANKG2CNKG2ESHP-1
Complex memberships
CD94/NKG2A inhibitory receptorCD94/NKG2C-DAP12 activating receptorCD94/NKG2E activating receptor

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CD94 glycoproteins form disulfide-bonded heterodimers with NKG2A/B, NKG2C, and NKG2E glycoproteins. NKG2A/B possesses two ITIM sequences in its cytoplasmic domain responsible for inhibitory function, whereas other NKG2 proteins lack ITIMs and may transmit positive signals. Biochemical co-immunoprecipitation, SDS-PAGE, sequence analysis of cytoplasmic domains Journal of immunology High 8943374
1996 CD94 exists in at least two biochemically and serologically distinct forms: an inhibitory form (~43 kDa, group B clones) and a stimulatory form (~39 kDa, group A clones). The inhibitory form is selectively recognized by the Z199 mAb. CD94 is assembled as a disulfide-linked dimer. Immunoprecipitation, SDS-PAGE, N-glycanase and V8 protease digestion, reverse ADCC functional assays Journal of immunology High 8955184
1997 The inhibitory NK cell receptor is a covalent heterodimer of CD94 and NKG2-A (~43 kDa). NKG2-B, an alternatively spliced product of NKG2-A, also assembles with CD94. Both NKG2-A and NKG2-B contain cytoplasmic ITIMs providing the molecular basis for inhibitory function. Co-immunoprecipitation with anti-CD94 mAb, SDS-PAGE, identification of NKG2-A protein, ITIM sequence analysis European journal of immunology High 9045931
1997 NKG2A (~43 kDa) is covalently associated with CD94 on the surface of NK cells. Cell surface expression of NKG2A requires association with CD94 (as glycosylation patterns characteristic of mature proteins are found only in NKG2A associated with CD94). NKG2A contains two ITIMs consistent with its inhibitory function. Co-immunoprecipitation, glycosylation analysis, NK clone functional analysis The Journal of experimental medicine High 9034158
1997 CD94 ligation on group A (activating) NK clones induces activation of intracellular PTKs (lck and ZAP-70), phospholipase C, and PI3-kinase. In contrast, CD94 ligation on group B (inhibitory) clones inhibits FcR-induced tyrosine phosphorylations of ZAP-70 and PLC-γ2, formation of phospho-zeta/ZAP-70 complexes, and release of inositol phosphates. Biochemical signaling assays, kinase activation assays, phosphorylation studies on sorted NK clones Journal of immunology High 8816383
1998 HLA-E tetramers bind specifically to CD94/NKG2A, CD94/NKG2B, and CD94/NKG2C NK cell receptor complexes on transfectants, but not to immunoglobulin-family KIR receptors. Surface expression of HLA-E is sufficient to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. HLA-E tetramer binding to transfectants, NK cytotoxicity assays with antibody blocking Nature High 9486650
1998 HLA-E is a major ligand for the CD94/NKG2A inhibitory receptor complex. Stabilization of HLA-E surface expression by appropriate HLA class I leader sequence peptides is sufficient to confer protection from NK lysis via CD94/NKG2A recognition. The inhibitory interaction is not mediated through Ig-SF KIRs or ILT2/LIR1. NK cytotoxicity assays, antibody blocking with anti-HLA-E, anti-CD94, anti-CD94/NKG2A mAbs; cold-target loading with leader peptides Proceedings of the National Academy of Sciences High 9560253
1998 CD94/NKG2C (activating receptor) noncovalently associates with DAP12, a membrane receptor containing an ITAM. Efficient surface expression of CD94/NKG2C requires DAP12. Charged residues in the transmembrane domains of DAP12 and NKG2C are necessary for this interaction. Co-immunoprecipitation, transfection with wild-type and mutant constructs, surface expression analysis Immunity High 9655483
1998 Specific engagement of CD94/NKG2-A by HLA-E induces tyrosine phosphorylation of the NKG2-A subunit and SHP-1 recruitment. These early biochemical events were also detected upon NK cell interaction with HLA-E+ transfectants and were prevented by anti-HLA class I mAb. In RBL-2H3 transfectants, CD94/NKG2-A cross-linking promoted NKG2-A tyrosine phosphorylation, SHP-1 co-precipitation, and inhibition of Fc-εRI-triggered secretion. Tyrosine phosphorylation assays, SHP-1 co-immunoprecipitation, RBL-2H3 transfection reconstitution, cytotoxicity assays European journal of immunology High 9565368
1998 Mouse NKG2A forms a CD94/NKG2A heterodimer that directly recognizes the nonclassical MHC class Ib molecule Qa-1(b) in a peptide (Qdm)-dependent manner, leading to inhibition of NK-mediated target cell lysis. Qa-1(b) tetramer binding, cloning of mouse NKG2A, NK cytotoxicity assays with peptide loading The Journal of experimental medicine High 9815261
1998 The activating CD94/NKG2C receptor complex is formed by covalent association of CD94 with NKG2-C (Kp39). COS7 cotransfection of CD94 and NKG2-C confirmed the identity of Kp39 as NKG2-C. The P25 mAb triggered cytolytic activity via this complex in redirected killing. Co-immunoprecipitation, COS7 co-transfection, peptide mapping, RT-PCR on NK clones, redirected killing assay European journal of immunology High 9485212
1999 The inhibitory CD94/NKG2-A receptor has a higher binding affinity for HLA-E than the activating CD94/NKG2-C receptor. Both receptors show very fast association and dissociation kinetics. Recognition of HLA-E by both receptors is peptide-dependent, and binding affinity of peptide-HLA-E complexes directly correlates with triggering of NK cell responses. Surface plasmon resonance (BIAcore) with soluble recombinant HLA-E and soluble CD94/NKG2-A and CD94/NKG2-C proteins; NK functional assays The EMBO journal High 10428963
1999 The crystal structure of the CD94 extracellular domain reveals a unique C-type lectin fold variation in which the second alpha-helix is replaced by a loop, the putative carbohydrate-binding site is altered, and the Ca2+-binding site appears nonfunctional. The CD94 dimer observed in the crystal has an extensive hydrophobic interface and reveals a putative ligand-binding region for HLA-E, suggesting how NKG2 interacts with CD94. X-ray crystallography at 2.6 Å resolution Immunity High 10023772
1999 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk kinase activation and tyrosine phosphorylation of the CD16 zeta subunit. It also inhibits ERK activation by blocking Shc tyrosine phosphorylation and Shc/Grb-2 complex formation downstream of CD16. Kinase activity assays, co-immunoprecipitation, western blotting for phosphorylation, ERK activation assays Journal of immunology High 10358164
1999 Mouse CD94/NKG2C and CD94/NKG2E also bind to Qa-1(b), and these are activating receptors based on cytoplasmic domain features. An anti-NKG2 blocking mAb demonstrated that CD94/NKG2 molecules are the only Qa-1(b) receptors on NK cells. Cloning and expression, Qa-1(b) binding assays, anti-NKG2 blocking mAb, RT-PCR The Journal of experimental medicine High 10601355
1998 HLA-E is expressed on the surface of trophoblast cells and the majority of decidual NK cells bind HLA-E tetramers; this binding is inhibited by anti-CD94 mAb. The overall functional consequence of CD94/NKG2 interaction with HLA-E on decidual NK cells is inhibition of cytotoxicity. HLA-E tetramer binding, flow cytometry, anti-CD94 blocking, cytotoxicity assays with decidual NK cells European journal of immunology High 10898498
2002 CD94/NKG2A receptors continuously recycle between the cell surface and intracellular endosomal compartments in an active process requiring energy and the cytoskeleton. CD94/NKG2A uses a distinct recycling compartment from transferrin receptor. CD94/NKG2A internalization is independent of ligand cross-linking or functional ITIM motifs. Flow cytometry, confocal microscopy, biochemical fractionation, transfection of wild-type and ITIM-mutant CD94/NKG2A in RBL-2H3 cells Journal of immunology High 12444112
2006 CD94/NKG2A engagement prevents NK cell activation by disrupting the actin network and excluding lipid rafts at the inhibitory NK immunological synapse (iNKIS). This involves SHP-1 recruitment and activation, leading to dephosphorylation of Vav1 and ezrin-radixin-moesin (ERM) proteins. Actin polymerization inhibition abolished lipid raft exclusion at iNKIS, whereas cholesterol depletion did not affect actin disruption. Confocal microscopy, fluorescence imaging of immunological synapse, phosphorylation assays (Vav1, ERM), pharmacological inhibition of actin polymerization and cholesterol depletion Journal of immunology High 16951318
2007 Crystal structure of CD94-NKG2A heterodimer at 2.5 Å resolution reveals an asymmetric dimer interface despite structural homology between the two subunits, providing structural basis for preferred heterodimeric assembly. Extensive mutagenesis studies on HLA-E and CD94-NKG2A establish that the invariant CD94 chain plays a dominant role in interacting with HLA-E compared to the variable NKG2 chain. X-ray crystallography at 2.5 Å, site-directed mutagenesis of HLA-E and CD94-NKG2A interface residues Immunity High 18083576
2008 Crystal structure of CD94-NKG2A in complex with HLA-E (bound to HLA-G leader peptide) shows that the CD94 subunit dominates the interaction with HLA-E, while NKG2A is more peripheral to the interface. CD94 dominates peptide-mediated contacts with poor surface and chemical complementarity. The interaction shows little conformational change upon ligation ('lock and key' mode). Mutagenesis data confirmed the CD94-NKG2A-HLA-E interface. X-ray crystallography of ternary complex, mutagenesis at CD94-NKG2A-HLA-E interface The Journal of experimental medicine High 18332182
2008 Crystal structure of NKG2A/CD94/HLA-E at 4.4 Å resolution reveals that the C-terminal region of the bound peptide interacts entirely with CD94 (the invariant component). Residues 167-170 of NKG2A/C (at the CD94 heterodimer interface, not contacting HLA-E directly) account for the ~6-fold higher affinity of inhibitory NKG2A/CD94 compared to activating NKG2C/CD94 for HLA-E. X-ray crystallography at 4.4 Å, comparative analysis with NKG2C structure, evolutionary analysis Proceedings of the National Academy of Sciences High 18448674
2008 Subtle changes in peptide conformation (without changes in HLA-E heavy chain conformation) profoundly affect CD94-NKG2 receptor recognition of HLA-E. Structures of HLA-E with HLA-Cw*07 leader peptide (low affinity) versus HLA-G*01 leader peptide (high affinity) at 2.5 Å show allotypic variations produce subtle differences in peptide conformation within the binding groove. X-ray crystallography of two HLA-E/peptide complexes at 2.5 Å resolution, compared with CD94-NKG2 binding data Journal of molecular biology High 18339401
2004 Both CD94/NKG2A (inhibitory) and CD94/NKG2C (activating) bind the top of HLA-E alpha1/alpha2 domain using mostly shared but partly distinct sets of HLA-E residues. Two HLA-E mutations (D69A and H155A) selectively abrogated binding to CD94/NKG2A but not to CD94/NKG2C, identifying differential contact residues. Alanine-scanning mutagenesis of HLA-E with binding assays to soluble CD94/NKG2A and CD94/NKG2C European journal of immunology High 14971033
2000 CD69-triggered ERK activation and cell degranulation are negatively regulated by co-engagement of the CD94/NKG2-A inhibitory receptor. CD94/NKG2-A suppresses CD69-triggered degranulation by inhibiting ERK activation in RBL transfectants expressing both receptors. RBL-2H3 transfectants expressing CD69 and CD94/NKG2-A, ERK activation assays, degranulation assays, cytotoxicity assays European journal of immunology High 10671222
1999 HLA-E engagement of CD94/NKG2 complex on porcine endothelial cell transfectants leads to phosphorylation of the CD94/NKG2 complex and recruitment of SHP-1, mediating inhibition of xenoreactive human NK cells. In contrast, HLA-G inhibits NK cells through a CD94/NKG2-independent pathway without SHP-1 recruitment. Anti-CD94 blocking, SHP-1 co-immunoprecipitation, phosphorylation assays, xenogeneic cytotoxicity assays Journal of immunology Medium 10570324
2003 Hsp70 protein and its C-terminal domain (Hsp70C) bind specifically to CD94 on NK cells (YT cell line). CD94-specific antibody completely abrogated Hsp70 binding. Competition assays with excess unlabeled Hsp70 (not unrelated GST) confirmed specific, concentration-dependent binding. Immunofluorescence binding studies, antibody blocking with anti-CD94 mAb, competition assays Biological chemistry Medium 12675520
2011 CD94 is essential for resistance of C57BL/6 mice to ectromelia virus (mousepox). Ectromelia virus-infected cells expressing Qa-1(b) are specifically recognized by the activating receptor CD94-NKG2E, and CD94-deficient mice are highly susceptible to mousepox. CD94-deficient mouse infection model, NK cell depletion, genetic epistasis, survival/viral load assays Immunity High 21439856
2010 CD94-deficient mice develop NK cells normally that efficiently kill NK-susceptible targets. Lack of CD94 receptors (and associated NKG2A, NKG2C, NKG2E) does not alter control of mouse CMV, LCMV, vaccinia virus, or Listeria monocytogenes, indicating CD94 is dispensable for NK cell development, education, and many innate immune functions. Gene-targeted CD94-deficient mouse, NK cell development and functional assays, viral and bacterial infection challenge models PloS one High 21151939
2005 CD94/NKG2C is coupled to DAP12 (KARAP) in CD8+ T cells, and specific engagement of CD94/NKG2C triggers cytotoxicity, cytokine production, IL-2Rα expression, and proliferative responses in CD94/NKG2C+ T cell clones. Anti-CD94 co-precipitation confirmed DAP12 association in T cells. Co-immunoprecipitation of DAP12 with anti-CD94, functional assays (cytotoxicity, cytokine production, proliferation) in T cell clones with selective receptor engagement European journal of immunology Medium 15940674
2002 Mouse Nkg2a is stochastically and monoallelically expressed, similar to Ly49 genes. DBA/2J mice are naturally CD94-deficient and do not express surface CD94/NKG2A receptors. CD94-deficient neonatal NK cells are self-tolerant, indicating self-tolerance of neonatal NK cells cannot be solely attributed to CD94/NKG2A expression. Allele-specific expression analysis, DBA/2J strain characterization, flow cytometry Proceedings of the National Academy of Sciences Medium 11782535
2021 NKG2A genetic ablation in dams mated with wild-type males causes suboptimal maternal vascular responses in pregnancy, perturbed placental gene expression, reduced fetal weight, and abnormal fetal brain development. These results establish that the HLA-B→HLA-E→NKG2A pathway contributes to healthy pregnancy via NK cell education. NKG2A gene-targeted KO mouse crossed with wild-type males, vascular/placental/fetal phenotyping, genome-wide association study in humans for validation Immunity High 33887202
2005 CD94/NKG2A receptors move freely within the plasma membrane, accumulate at the site of contact with ligand-bearing target cells, and continuously recycle from the cell surface through endosomal compartments in a process requiring energy and the cytoskeleton. Lipid raft marker cholera toxin B is excluded from CD94/NKG2A-enriched contact sites; methylcyclodextrin does not interfere with CD94/NKG2A accumulation at contact sites. FRAP, live-cell fluorescence microscopy, pharmacological perturbations (cytoskeleton inhibitors, cholesterol depletion), confocal microscopy Molecular immunology High 15607803
2002 CD94-NKG2A up-regulation on antiviral CD8+ T cells during acute polyoma virus infection is responsible for down-regulating their antigen-specific cytotoxicity during viral clearance and virus-induced oncogenesis. Murine polyoma virus infection model, flow cytometry of CD94/NKG2A expression on antigen-specific T cells, antibody blocking of CD94, cytotoxicity assays Nature immunology High 11812997
1998 IL-15 induces de novo expression of CD94 by T cells responding to superantigens; the simultaneous expression of NKG2A (forming functional CD94/NKG2A) is confined to CD8+ cells. Expression of CD94/NKG2A led to impairment of allo-specific cytolytic activity, which was restored by anti-CD94 mAb. In vitro T cell stimulation with superantigens in presence of IL-15, flow cytometry, cytotoxicity assays with anti-CD94 mAb blocking Proceedings of the National Academy of Sciences Medium 9448304
1999 TGF-β induces expression of CD94/NKG2A in T cells responding to bacterial superantigens. Expression preferentially occurs at low TGF-β concentrations, NKG2A expression is mostly confined to CD8+ cells, and mAb-mediated cross-linking of CD94/NKG2A impairs T cell triggering via CD3. In vitro stimulation of T cells with superantigens + TGF-β, flow cytometry, redirected killing assay European journal of immunology Medium 9933082
2024 LAG-3 sustains CD94/NKG2A expression on exhausted CD8 T cells by maintaining TOX expression. A LAG-3-dependent circuit generates a CD94/NKG2+ subset of exhausted T cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b (and HLA-E in humans). LAG-3 genetic deletion during chronic LCMV infection, single-cell analysis, functional cytotoxicity assays, Qa-1b blocking, TOX expression analysis Cell High 39121847
2020 NKG2A/CD94 was identified as a cognate receptor for HLA-G*01:01, with binding affinity dependent on the amino acid composition of the HLA-G heavy chain (HLA-G*01:04 shows highest affinity, while HLA-G*01:03 and HLA-G*01:01 show lower binding). Ligand-based receptor capture on living NK cells using sHLA-G*01:01 coupled to TriCEPS followed by mass spectrometry; reciprocal validation with recombinant soluble NKG2A/CD94 targeting HLA-G-expressing K562 cells International journal of molecular sciences Medium 32575403
2023 Among 16 common classical HLA class I signal peptide variants, only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement ('functional SPs'). The single functional HLA-B SP (HLA-B/-21M) confers the lowest receptor recognition by CD94/NKG2A/C despite inducing high HLA-E expression, because it competes with other SPs and reduces overall CD94/NKG2-HLA-E engagement. Systematic quantitative functional assays measuring HLA-E surface expression and CD94/NKG2A/C receptor engagement for all 16 common SP variants; competitive peptide loading assays Nature immunology High 37264229
1998 The human CD94 gene contains six exons separated by five introns. The carbohydrate-recognition domain (CRD) is encoded by three exons. Transcription initiation is heterogeneous but restricted to a 60 bp region within a putative initiator element. CD94 is closely related to group V of C-type lectins based on intron position conservation within the CRD. Genomic cloning, exon-intron structure determination, primer extension, S1 nuclease protection assays Immunogenetics Medium 9472066

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1823 9486650
1998 HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences of the United States of America 844 9560253
1998 Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 432 9655483
1998 Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b). The Journal of experimental medicine 357 9815261
2005 Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 356 16384928
1996 Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. Journal of immunology (Baltimore, Md. : 1950) 352 8943374
1999 Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. The EMBO journal 301 10428963
1999 The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. European journal of immunology 300 9933109
2000 HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. European journal of immunology 290 10898498
2023 Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer cell 272 36706761
1997 The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. European journal of immunology 251 9045931
1994 Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles. The Journal of experimental medicine 223 8046333
1997 NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. The Journal of experimental medicine 214 9034158
2009 CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood 197 19897577
1998 HLA class I-specific inhibitory receptors in human T lymphocytes: interleukin 15-induced expression of CD94/NKG2A in superantigen- or alloantigen-activated CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 194 9448304
2008 CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence. The Journal of experimental medicine 193 18332182
2003 The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. European journal of immunology 193 12778484
1999 CD69 is a stimulatory receptor for natural killer cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology 185 10447727
2008 Structural basis for NKG2A/CD94 recognition of HLA-E. Proceedings of the National Academy of Sciences of the United States of America 180 18448674
2002 IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. The Journal of clinical investigation 175 12438449
1999 Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells. The Journal of experimental medicine 167 10601355
2004 Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. Journal of immunology (Baltimore, Md. : 1950) 164 15528343
1999 Transforming growth factor-beta-induced expression of CD94/NKG2A inhibitory receptors in human T lymphocytes. European journal of immunology 163 9933082
2002 CD94-NKG2A receptors regulate antiviral CD8(+) T cell responses. Nature immunology 160 11812997
2003 Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biological chemistry 151 12675520
2012 Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A. PloS one 148 22384114
1997 Interleukin-15-induced maturation of human natural killer cells from early thymic precursors: selective expression of CD94/NKG2-A as the only HLA class I-specific inhibitory receptor. European journal of immunology 138 9209487
1996 CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles: identification of the inhibitory form of CD94 by the use of novel monoclonal antibodies. European journal of immunology 133 8898964
1997 CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 129 9550399
1997 Structure and function of the CD94 C-type lectin receptor complex involved in recognition of HLA class I molecules. Immunological reviews 120 9059892
2006 The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance. Immunologic research 119 17172651
2016 Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. Oncoimmunology 116 27853650
1999 Structure of CD94 reveals a novel C-type lectin fold: implications for the NK cell-associated CD94/NKG2 receptors. Immunity 111 10023772
1999 Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161. Archives of dermatology 110 10328195
1997 The CD94/NKG2-A inhibitory receptor complex is involved in natural killer cell-mediated recognition of cells expressing HLA-G1. Journal of immunology (Baltimore, Md. : 1950) 109 9190923
2002 TCR specificity dictates CD94/NKG2A expression by human CTL. Immunity 108 12387742
1998 Specific engagement of the CD94/NKG2-A killer inhibitory receptor by the HLA-E class Ib molecule induces SHP-1 phosphatase recruitment to tyrosine-phosphorylated NKG2-A: evidence for receptor function in heterologous transfectants. European journal of immunology 101 9565368
2001 The repertoire of killer cell Ig-like receptor and CD94:NKG2A receptors in T cells: clones sharing identical alpha beta TCR rearrangement express highly diverse killer cell Ig-like receptor patterns. Journal of immunology (Baltimore, Md. : 1950) 100 11238637
1998 Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proceedings of the National Academy of Sciences of the United States of America 100 9600963
2004 The role of CD94/NKG2 in innate and adaptive immunity. Immunologic research 98 15258309
2014 The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Seminars in immunology 94 24666761
2011 CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 93 21439856
1998 The activating form of CD94 receptor complex: CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene. European journal of immunology 93 9485212
2008 Subtle changes in peptide conformation profoundly affect recognition of the non-classical MHC class I molecule HLA-E by the CD94-NKG2 natural killer cell receptors. Journal of molecular biology 88 18339401
2003 Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell stress & chaperones 88 15115287
2024 LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 86 39121847
2006 CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 85 16951318
2007 The heterodimeric assembly of the CD94-NKG2 receptor family and implications for human leukocyte antigen-E recognition. Immunity 82 18083576
2011 Clinical significance of the HLA-E and CD94/NKG2 interaction. Archivum immunologiae et therapiae experimentalis 81 21800130
1997 HLA-G recognition by human natural killer cells. Involvement of CD94 both as inhibitory and as activating receptor complex. European journal of immunology 81 9295021
2019 Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses. Cancer immunology research 80 31213473
2004 The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partly distinct sets of HLA-E residues. European journal of immunology 79 14971033
2007 High expression of NKG2A/CD94 and low expression of granzyme B are associated with reduced cord blood NK cell activity. Cellular & molecular immunology 77 17976318
2013 NKG2C zygosity influences CD94/NKG2C receptor function and the NK-cell compartment redistribution in response to human cytomegalovirus. European journal of immunology 76 24030638
2021 The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice. Immunity 74 33887202
2005 The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. European journal of immunology 74 15940674
2002 Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood 73 12480700
2005 The cell biology of the human natural killer cell CD94/NKG2A inhibitory receptor. Molecular immunology 71 15607803
2002 Conservation and variation in human and common chimpanzee CD94 and NKG2 genes. Journal of immunology (Baltimore, Md. : 1950) 71 11751968
2002 Implications of CD94 deficiency and monoallelic NKG2A expression for natural killer cell development and repertoire formation. Proceedings of the National Academy of Sciences of the United States of America 67 11782535
2019 The inhibitory receptor CD94/NKG2A on CD8+ tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE/β2m overexpression. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 66 31409873
2009 IL-12-dependent inducible expression of the CD94/NKG2A inhibitory receptor regulates CD94/NKG2C+ NK cell function. Journal of immunology (Baltimore, Md. : 1950) 65 19124726
2011 Soluble HLA-G dampens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56bright and CD56dim NK cells. Blood 63 21989990
1999 Differential regulation of killer cell Ig-like receptors and CD94 lectin-like dimers on NK and T lymphocytes from HIV-1-infected individuals. European journal of immunology 62 10229073
2018 KLRD1-expressing natural killer cells predict influenza susceptibility. Genome medicine 61 29898768
2000 CD69-triggered ERK activation and functions are negatively regulated by CD94 / NKG2-A inhibitory receptor. European journal of immunology 59 10671222
1999 Cutting edge: expression of functional CD94/NKG2A inhibitory receptors on fetal NK1.1+Ly-49- cells: a possible mechanism of tolerance during NK cell development. Journal of immunology (Baltimore, Md. : 1950) 58 10358137
2023 HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses. Nature immunology 57 37264229
2002 Expression of CD94/NKG2-A on human T lymphocytes is induced by IL-12: implications for adoptive immunotherapy. Journal of immunology (Baltimore, Md. : 1950) 57 11994435
2006 Expression patterns of lectin-like natural killer receptors, inhibitory CD94/NKG2A, and activating CD94/NKG2C on decidual CD56bright natural killer cells differ from those on peripheral CD56dim natural killer cells. Journal of reproductive immunology 55 16488482
2003 Expression of CD94-NKG2A inhibitory receptor is restricted to a subset of CD8+ T cells. Trends in immunology 55 12697440
1998 Participation of the CD94 receptor complex in costimulation of human natural killer cells. Journal of immunology (Baltimore, Md. : 1950) 55 9469418
2004 Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR alphabeta lymphocytes. European journal of immunology 54 15517612
2010 CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. The Journal of allergy and clinical immunology 51 20132973
1999 HLA-E and HLA-G expression on porcine endothelial cells inhibit xenoreactive human NK cells through CD94/NKG2-dependent and -independent pathways. Journal of immunology (Baltimore, Md. : 1950) 51 10570324
1996 Clonotypic differences in signaling from CD94 (kp43) on NK cells lead to divergent cellular responses. Journal of immunology (Baltimore, Md. : 1950) 50 8816383
2002 Expression of inhibitory receptors Ly49E and CD94/NKG2 on fetal thymic and adult epidermal TCR V gamma 3 lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 47 11907085
2001 Expression of Ly49E and CD94/NKG2 on fetal and adult NK cells. Journal of immunology (Baltimore, Md. : 1950) 47 11254682
2005 IFN-gamma-mediated negative feedback regulation of NKT-cell function by CD94/NKG2. Blood 46 15746081
2001 The KIR and CD94/NKG2 families of molecules in the rhesus monkey. Immunological reviews 44 11782245
2001 Ly49 and CD94/NKG2: developmentally regulated expression and evolution. Immunological reviews 42 11513155
1996 Biochemical and serologic evidence for the existence of functionally distinct forms of the CD94 NK cell receptor. Journal of immunology (Baltimore, Md. : 1950) 42 8955184
2010 Development and function of CD94-deficient natural killer cells. PloS one 41 21151939
2000 Expression of CD94/NKG2A and killer immunoglobulin-like receptors in NK cells and a subset of extranodal cytotoxic T-cell lymphomas. Blood 41 10828054
2020 High CD26 and Low CD94 Expression Identifies an IL-23 Responsive Vδ2+ T Cell Subset with a MAIT Cell-like Transcriptional Profile. Cell reports 39 32553157
2007 Increased frequency of human leukocyte antigen-E inhibitory receptor CD94/NKG2A-expressing peritoneal natural killer cells in patients with endometriosis. Fertility and sterility 39 17706207
2011 Selenite induces posttranscriptional blockade of HLA-E expression and sensitizes tumor cells to CD94/NKG2A-positive NK cells. Journal of immunology (Baltimore, Md. : 1950) 38 21890659
1999 CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 37 10358164
2014 Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. Immunology 36 24673109
2006 Coengagement of CD16 and CD94 receptors mediates secretion of chemokines and induces apoptotic death of naive natural killer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 36 16609008
2005 Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway. Biochemical pharmacology 36 15978547
1998 Phosphoantigen activation induces surface translocation of intracellular CD94/NKG2A class I receptor on CD94- peripheral Vgamma9 Vdelta2 T cells but not on CD94- thymic or mature gammadelta T cell clones. European journal of immunology 36 9842883
2002 NK cell CD94/NKG2A inhibitory receptors are internalized and recycle independently of inhibitory signaling processes. Journal of immunology (Baltimore, Md. : 1950) 34 12444112
2020 NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain. International journal of molecular sciences 33 32575403
2007 Reconstitution of natural killer cell receptor repertoires after unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation: analyses of CD94:NKG2A and killer immunoglobulin-like receptor expression and their associations with clinical outcome. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 33 17531784
2005 The role of TCR stimulation and TGF-beta in controlling the expression of CD94/NKG2A receptors on CD8 T cells. European journal of immunology 33 15714583
2002 Orderly and nonstochastic acquisition of CD94/NKG2 receptors by developing NK cells derived from embryonic stem cells in vitro. Journal of immunology (Baltimore, Md. : 1950) 33 11994449
2002 CD94/NKG2 expression does not inhibit cytotoxic function of lymphocytic choriomeningitis virus-specific CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 33 12097371
1998 Structure of the human CD94 C-type lectin gene. Immunogenetics 33 9472066
2021 CD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn's disease. Nature communications 32 34615883

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