Affinage

HLA-E

HLA class I histocompatibility antigen, alpha chain E · UniProt P13747

Length
358 aa
Mass
40.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLA-E is a non-classical MHC class I molecule that functions as a sentinel of antigen-processing pathway integrity and cellular stress by presenting a restricted repertoire of peptides—primarily nonameric sequences derived from MHC class I signal peptides—to the inhibitory receptor CD94/NKG2A and the activating receptor CD94/NKG2C on NK cells and CD8+ T cells (PMID:9560253, PMID:9660937, PMID:11714810). HLA-E assembles with β2-microglobulin and peptide in the ER via TAP-dependent loading of signal peptide fragments generated by signal peptide peptidase; it is largely ER-retained due to limited high-affinity peptide supply, and its cytoplasmic tail drives rapid endocytosis when the molecule reaches the cell surface (PMID:9574542, PMID:37140910). The identity of the bound peptide determines functional outcome: canonical MHC class I leader peptides engage CD94/NKG2A to inhibit NK cell cytotoxicity, whereas pathogen-derived peptides (from HIV capsid, SARS-CoV-2 Nsp13, or M. tuberculosis) or stress-induced peptides (hsp60 signal peptide) adopt alternative conformations that fail to engage the inhibitory receptor, thereby licensing NK cell killing of infected or stressed targets (PMID:12461076, PMID:26828202, PMID:35705051, PMID:35235832). This peptide-dependent checkpoint is exploited by HCMV UL40, which supplies an HLA-E-binding peptide independently of TAP to maintain inhibitory signaling during viral immune evasion, and by tumors and senescent cells that upregulate HLA-E to escape NKG2A+ effector responses (PMID:10669413, PMID:31160572, PMID:36706761).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Identification of HLA-E as the principal ligand for CD94/NKG2A established the functional role of this non-classical MHC molecule as an NK cell inhibitory checkpoint, resolving the question of which molecule presented self-information to CD94-bearing receptors.

    Evidence NK cytotoxicity assays with HLA-E transfectants and blocking antibodies against CD94/NKG2A; crystal structure of HLA-E/β2m/peptide complex at 2.85 Å revealing constrained peptide specificity for MHC class I leader sequences; TAP interaction and peptide binding biochemistry

    PMID:9560253 PMID:9574542 PMID:9660937

    Open questions at the time
    • Mechanism of HLA-E trafficking from ER to surface was not yet defined
    • Whether HLA-E engages CD94/NKG2C with distinct functional consequences was unresolved
    • In vivo physiological relevance beyond cell line assays not established
  2. 2000 High

    Discovery that HCMV UL40 provides a TAP-independent peptide to stabilize HLA-E and that HLA-E functions on trophoblasts revealed pathogen exploitation and physiological immune tolerance roles for the HLA-E/NKG2A axis.

    Evidence HCMV infection with TAP-deficient cell lines showing TAP-independent HLA-E loading by UL40 leader peptide; HLA-E tetramer binding and cytotoxicity assays with decidual NK cells

    PMID:10669413 PMID:10898498

    Open questions at the time
    • Structural basis for UL40 peptide mimicry of host leader sequences not yet determined
    • Whether other viruses employ similar evasion strategies was unknown
    • Trophoblast HLA-E peptide repertoire not defined
  3. 2001 High

    Identification of signal peptide peptidase as the protease generating HLA-E epitopes from MHC class I signal sequences resolved how the immune system couples classical MHC class I biosynthesis to non-classical HLA-E-mediated NK surveillance.

    Evidence Signal peptide peptidase inhibition blocking release of epitope-containing fragment from the lipid bilayer, with demonstration of subsequent TAP-dependent ER transport

    PMID:11714810

    Open questions at the time
    • Whether signal peptide peptidase activity is rate-limiting for HLA-E surface expression was unclear
    • Contribution of other ER-resident proteases not excluded
  4. 2002 High

    Discovery that HLA-E presents an hsp60-derived signal peptide unrecognized by CD94/NKG2A demonstrated that HLA-E acts as a stress sensor, not merely a reporter of MHC class I biosynthesis, fundamentally broadening its immunological role.

    Evidence HLA-E/hsp60 peptide complex characterization with CD94/NKG2A binding and NK functional assays on stressed cells; allelic comparison crystal structures showing that peptide identity rather than heavy chain conformation determines receptor engagement

    PMID:12411439 PMID:12461076

    Open questions at the time
    • Range of stress-induced peptides binding HLA-E was not systematically catalogued
    • Whether hsp60 peptide engages NKG2C was unknown
  5. 2008 High

    Crystal structures of the CD94/NKG2A–HLA-E complex revealed that CD94 dominates the interaction interface and peptide contacts, while NKG2A residues 167–170 account for the higher affinity over NKG2C, explaining the molecular basis for differential inhibitory vs. activating receptor engagement.

    Evidence X-ray crystallography of CD94-NKG2A/HLA-E at 3.5 Å and 4.4 Å with mutagenesis validation and affinity measurements; parallel structures of HLA-E with peptides showing that subtle peptide conformational differences dictate receptor recognition

    PMID:18332182 PMID:18339401 PMID:18448674

    Open questions at the time
    • Full structure of CD94/NKG2C–HLA-E complex not yet solved
    • How peptide conformational differences translate to signaling outcomes remained unclear
  6. 2015 High

    Systematic analyses of HLA-E allelic peptide repertoires and NK cell subset responses demonstrated that NKG2A inhibition is broadly permissive for diverse peptides while NKG2C activation is selectively triggered by restricted peptide identities, establishing the asymmetric peptide-selectivity principle governing the HLA-E checkpoint.

    Evidence Mass spectrometric HLA-E ligandome for E*01:01 vs. E*01:03; degranulation assays with NKG2A+ and NKG2C+ NK subsets across panels of HLA-E–peptide complexes; in vivo myeloma xenograft showing microenvironment-driven HLA-E upregulation inhibiting NKG2A+ NK cells

    PMID:25920521 PMID:26382247 PMID:26552660

    Open questions at the time
    • Structural explanation for NKG2C peptide selectivity lacking
    • How HLA-E allelic differences affect disease outcomes not established in patient cohorts
  7. 2016 High

    Demonstration that HLA-E presents an HIV capsid peptide not recognized by NKG2A revealed that pathogen-derived peptides can convert HLA-E from an inhibitory to a permissive ligand, directly licensing NK killing of HIV-infected cells.

    Evidence Cytolytic assays with autologous primary NK cells against HIV-infected T cells with HLA-E peptide loading and NKG2A blocking

    PMID:26828202

    Open questions at the time
    • Breadth of HIV-derived HLA-E epitopes unknown
    • Whether HIV-specific NK responses are durable in vivo was unresolved
  8. 2017 High

    Discovery that HLA-E presents a mannosylated M. tuberculosis glycopeptide to CD8+ T cells expanded the antigen repertoire to post-translationally modified bacterial antigens and established HLA-E-restricted T cell immunity as a component of anti-mycobacterial defense.

    Evidence CD8+ T cell clone characterization with mannosyltransferase (Rv1002c) knockout confirming glycosylation requirement for HLA-E presentation

    PMID:28676677

    Open questions at the time
    • Prevalence of HLA-E-restricted T cell responses in TB patients not quantified
    • Whether glycopeptide presentation follows the same loading pathway as signal peptides was unknown
  9. 2018 High

    Crystal structures of HLA-E with pathogen-derived peptides revealed conformational flexibility in the binding groove and broader anchor residue tolerance than anticipated, providing the structural explanation for how HLA-E accommodates both self-leader and diverse non-self peptides.

    Evidence X-ray crystallography of HLA-E with HIV and Mtb peptides with mutagenesis validation

    PMID:30087334

    Open questions at the time
    • Peptide exchange dynamics at the cell surface not characterized
    • How groove flexibility affects receptor engagement kinetics unknown
  10. 2019 High

    Multiple studies converged to show that HLA-E upregulation serves as an immune evasion strategy in senescence and viral infection: senescent cells upregulate HLA-E via p38/SASP signaling to inhibit NKG2A+ effectors, while HIV Nef targets the HLA-E cytoplasmic tail for downregulation, revealing the cytoplasmic tail as a key regulatory element.

    Evidence p38 inhibitor and NKG2A blocking antibody experiments in senescent fibroblasts; cytoplasmic tail swap experiments in HIV Nef-expressing cells

    PMID:31160572 PMID:31375574

    Open questions at the time
    • Specific motifs in the cytoplasmic tail required for Nef interaction not mapped
    • Whether senescence-induced HLA-E peptide repertoire differs from homeostatic repertoire was unclear
  11. 2022 High

    SARS-CoV-2 Nsp13 peptide was shown to abrogate HLA-E/NKG2A inhibitory signaling, licensing NK killing of infected cells, while structural studies revealed that non-VL9 peptides induce extended HLA-E conformations that disfavor NKG2A recognition, providing a unified structural-functional framework for peptide-dependent checkpoint control.

    Evidence HLA-E/Nsp13 peptide loading with NKG2A binding assays and viral replication suppression assays; crystallography and SAXS showing compact VL9-bound vs. extended non-VL9-bound HLA-E conformations

    PMID:35235832 PMID:35705051

    Open questions at the time
    • Whether conformational differences affect NKG2C engagement was not addressed
    • In vivo relevance of Nsp13 peptide presentation during COVID-19 not confirmed
  12. 2023 High

    Multiple advances defined the complete HLA-E trafficking cycle, the quantitative rules governing signal peptide competition, the breadth of the HLA-E peptidome, and the role of HLA-E/NKG2C in antigen-specific NK cell memory, collectively reframing HLA-E as a versatile immune surveillance hub beyond simple inhibitory checkpointing.

    Evidence Live-cell imaging and cytoplasmic tail mutants defining ER retention and rapid endocytic cycling; systematic SP variant analysis showing only 6 of 16 common SPs are functional; yeast-display library identifying 500 binding peptides; single-cell cloning of epitope-specific memory NK cells dependent on HLA-E/NKG2C; RGS18-AKT-CREB pathway driving tumor HLA-E upregulation for metastatic immune evasion

    PMID:36706761 PMID:37140910 PMID:37264229 PMID:37558657 PMID:38064568

    Open questions at the time
    • Full in vivo trafficking itinerary of HLA-E in different tissues not mapped
    • How memory NK cell TCR-like specificity for HLA-E–peptide is encoded at the molecular level remains unknown
    • Competition dynamics among signal peptides in physiological multi-allele settings not modeled

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the complete structural basis of CD94/NKG2C engagement with HLA-E, the in vivo peptide repertoire of HLA-E across tissues and disease states, the molecular mechanism of XPO1-dependent HLA-E surface regulation, and whether HLA-E-restricted adaptive NK memory can be therapeutically harnessed.
  • No crystal structure of CD94/NKG2C–HLA-E complex published
  • In vivo HLA-E peptidome from primary tissues not comprehensively determined
  • Mechanism linking XPO1 to HLA-E surface expression is correlative
  • Therapeutic exploitation of HLA-E/NKG2C memory axis untested in clinical settings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 4
Partners
B2MKLRC1KLRC2KLRD1SPPL3TAP1XPO1
Complex memberships
CD94/NKG2A/HLA-ECD94/NKG2C/HLA-EHLA-E/β2-microglobulin/peptide

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 HLA-E is the major ligand for the inhibitory NK cell receptor CD94/NKG2A. Surface stabilization of HLA-E with appropriate peptides confers protection from NK cell lysis mediated specifically through CD94/NKG2A, not through Ig-SF killer cell inhibitory receptors or ILT2/LIR1. NK cell cytotoxicity assays with HLA-E transfectants (.221 cells), antibody blocking of HLA-E, CD94, or CD94/NKG2A, cold-loading of peptides onto target cells Proceedings of the National Academy of Sciences of the United States of America High 9560253
1998 HLA-E crystal structure reveals that it binds a tightly defined set of nearly identical hydrophobic nonameric peptides derived from MHC class I leader sequences (prototypic: VMAPRTVLL), with novel structural features that enforce peptide-binding specificity and function as a checkpoint reporting on antigen processing pathway integrity to CD94/NKG2 receptors. X-ray crystallography of HLA-E/β2m/peptide complex at 2.85 Å resolution Molecular cell High 9660937
1998 HLA-E interacts with TAP in the endoplasmic reticulum for peptide loading, and this interaction can be prolonged by proteasome inhibition. HLA-E can bind peptides ranging from 7 to 16 amino acids, and the exact N-terminal positioning is critical for binding. Peptide binding assays measuring surface HLA-E expression, thermostability assays of soluble HLA-E/β2m dimers, TAP interaction studies with proteasome inhibitor N-acetyl-L-leucyl-L-leucyl-L-norleucinal Journal of immunology High 9574542
2000 Human cytomegalovirus glycoprotein UL40 (gpUL40) contains a leader sequence peptide identical to HLA class I signal sequences; this peptide loads HLA-E independently of TAP, upregulating HLA-E surface expression and protecting infected cells from NK cell lysis while classical MHC class I molecules are downregulated by HCMV. HCMV infection of cells, TAP-independent peptide loading demonstrated in TAP-deficient cell lines, NK cell cytotoxicity assays Science High 10669413
2000 HLA-E is expressed on trophoblast cell surfaces and interacts with CD94/NKG2 receptors on decidual NK cells, with the overall functional consequence being inhibition of decidual NK cell cytotoxicity. HLA-E tetrameric complex binding to decidual NK cells, anti-CD94 antibody blocking, cytotoxicity assays with polyclonal decidual NK cells European journal of immunology High 10898498
2001 MHC class I signal peptides are processed by signal peptide peptidase in the hydrophobic membrane-spanning region after cleavage from the pre-protein; this intramembrane proteolysis is essential for release of the HLA-E epitope-containing fragment from the lipid bilayer and its subsequent TAP-dependent transport into the ER lumen. Signal peptide peptidase inhibition experiments, biochemical fractionation, demonstration of TAP-dependent transport of the processed fragment Journal of immunology High 11714810
2002 HLA-E alleles (E*0101 with Arg107 vs. E*0103 with Gly107) differ in peptide affinity and thermal stability, which correlates with differential cell surface expression levels, but the crystal structures of HLA-E(G) with two peptides show no significant structural differences induced by peptide binding or allelic substitution at position 107. X-ray crystallography of HLA-E(G) allele with two peptides, thermal stability assays, cell surface expression analysis The Journal of biological chemistry High 12411439
2002 HLA-E presents a peptide derived from the leader sequence of heat shock protein 60 (hsp60), which gains access to HLA-E intracellularly during cellular stress. HLA-E/hsp60 signal peptide complexes are not recognized by CD94/NKG2A inhibitory receptors, thereby reducing NK cell inhibition and providing a mechanism for NK cells to detect stressed cells. HLA-E/hsp60 peptide complex characterization, CD94/NKG2A binding assays, NK cell functional assays with stressed cells The Journal of experimental medicine High 12461076
2003 HLA-E cell surface expression in tumor cells requires availability of free β2-microglobulin; tumors with imbalanced HLA class Ia heavy chain/β2m expression show increased HLA-E surface detection, while total loss of HLA class Ia expression abolishes HLA-E surface expression. FACS analysis with anti-HLA-E mAb (3D12) on tumor cell lines, exogenous β2m addition experiments, analysis of cell lines with defined HLA class I genetic alterations Immunogenetics Medium 12618909
2005 An HLA-E single-chain trimer (SCT) consisting of linked HLA-B leader peptide, β2m, and HLA-E heavy chain confers surface expression on porcine cells and protects them from NK cell lysis via CD94/NKG2A interaction; an SCT bearing the hsp60-derived peptide is expressed but does not inhibit NK lysis, demonstrating peptide-dependent functional specificity. HLA-E SCT transfection of LLC-PK1 porcine cells, NK cell cytotoxicity assays with NKL and NK-92 cell lines, IFN-γ secretion assays Molecular immunology High 15829309
2007 Gliadin peptides (alpha and omega fractions) stabilize HLA-E molecules on dendritic cells, protecting immature DCs from NK cell lysis and modulating NK-DC crosstalk; a peptide derived from gliadin alpha increases HLA-E levels on RMA-S/HLA-E-transfected cells. HLA-E surface expression analysis, NK cell cytotoxicity assays with gliadin-treated DCs, RMA-S/HLA-E transfectant loading assays, immunohistochemistry of intestinal mucosa from celiac patients Journal of immunology Medium 17579058
2008 Crystal structure of CD94-NKG2A in complex with HLA-E bound to HLA-G leader peptide reveals that CD94 dominates the interaction with HLA-E while NKG2A is more peripheral; the invariant CD94 subunit dominates peptide-mediated contacts; there are few conformational changes upon ligation ('lock and key' interaction). Mutagenesis at the CD94-NKG2A-HLA-E interface confirmed the structural contacts. X-ray crystallography of CD94-NKG2A/HLA-E complex at 3.5 Å, site-directed mutagenesis The Journal of experimental medicine High 18332182
2008 Crystal structure of NKG2A/CD94/HLA-E complex at 4.4 Å reveals that the C-terminal region of the peptide (most variable among class I leader sequences) interacts entirely with CD94, and residues 167-170 of NKG2A account for the ~6-fold higher affinity of NKG2A/CD94 versus NKG2C/CD94 through their role in the heterodimer interface with CD94 rather than direct HLA-E contact. X-ray crystallography, affinity measurements, binding assays with UL18 Proceedings of the National Academy of Sciences of the United States of America High 18448674
2008 Crystal structures of HLA-E with two leader peptides (HLA-Cw*07: VMAPRALLL, poorly recognized; HLA-G*01: VMAPRTLFL, high-affinity) at 2.5 Å show that allotypic variations do not alter HLA-E heavy chain conformation, but subtle changes in peptide conformation within the binding groove profoundly affect CD94-NKG2 receptor recognition. X-ray crystallography at 2.5 Å resolution for both complexes Journal of molecular biology High 18339401
2009 HLA-E surface expression on transgenic pig cells expressing HLA-E and human β2-microglobulin inhibits human NK cell-mediated cytotoxicity in a CD94/NKG2A-dependent manner and also inhibits IFN-γ secretion by co-cultured human NK cells. HLA-E/hβ2m transgenic pig generation, NK cell cytotoxicity assays, IFN-γ ELISA, FACS Transplantation High 19136889
2003 HLA-E-mediated inhibition of NK cell lysis requires peptide loading and is TAP-independent when specific signal sequence peptides are available: HCMV gpUS6, which blocks TAP by 95%, does not affect HLA-E surface expression or its ability to inhibit NK cell lysis via CD94/NKG2A, and HLA-E is functional on TAP-deficient RMA-S transfectants. gpUS6-expressing transfectants, TAP inhibition assays, NK cell cytotoxicity assays, HLA-E surface expression by FACS Human immunology High 12559625
2013 Polymorphisms in the HCMV UL40 leader sequence mimic region modulate the affinity of UL40-derived peptide/HLA-E complexes for CD94-NKG2 receptors; some UL40 peptide variants can inhibit NK lysis via CD94-NKG2A but have little capacity to activate NK cells through CD94-NKG2C, suggesting UL40 polymorphisms facilitate viral immune evasion by differential receptor engagement. UL40 sequencing from HSCT recipients, HLA-E/peptide binding affinity assays, NK cell clone cytotoxicity assays (NKG2A+ or NKG2C+ clones) The Journal of biological chemistry High 23335510
2015 HLA-E*01:01 and HLA-E*01:03 alleles present distinct and non-overlapping peptide repertoires (9-17 amino acids); differences in peptide stabilization capacity caused by the Arg107Gly substitution affect cell surface HLA-E density and half-life, which in turn impact NK cell inhibition as measured by cytotoxicity assays. Soluble HLA technology with mass spectrometric peptide sequencing (HLA-E*01:03 ligandome), artificial APCs expressing peptide-stabilized HLA-E, NK cell cytotoxicity assays Immunogenetics High 26552660
2016 HLA-E presents a conserved peptide from HIV-1 capsid (AISPRTLNA) that is not recognized by NKG2A/CD94, causing HIV-infected T cells to be susceptible to killing by NKG2A/CD94+ NK cells despite high HLA-E surface expression; NKG2A/CD94+ NK cells generate the most efficient responses against HIV-infected T cells. In vitro cytolytic assays with autologous primary NK cells and HIV-infected primary T cells, HLA-E peptide loading with HIV capsid peptide, NKG2A/CD94 blocking PLoS pathogens High 26828202
2018 HLA-E presents diverse pathogen-derived peptides (HIV and Mtb) with conformational flexibility: pathogen-derived peptides adopt alternative conformations within the HLA-E binding groove, and mutagenesis reveals greater tolerance for hydrophobic and polar residues in primary anchor pockets than previously appreciated. X-ray crystallography of HLA-E with HIV- and Mtb-derived peptides, mutagenesis, biochemical peptide binding studies Nature communications High 30087334
2018 Adaptive NK cells discriminate between different HLA-E peptide complexes with exquisite specificity via CD94/NKG2C; prolonged exposure to HLA-E/VMAPRTLFL (HLA-G leader peptide) enriches adaptive NK cells with altered signaling molecule expression and elevated antibody-dependent cellular cytotoxicity and IFN-γ responses. Flow cytometry, ADCC assays, IFN-γ ELISA, comparison of NK cell function with different HLA-E peptide complexes Cell reports High 30134159
2019 Senescent dermal fibroblasts upregulate HLA-E expression via senescence-associated secretory phenotype (SASP)-related pro-inflammatory cytokines through p38 MAP kinase signaling; HLA-E on senescent cells interacts with NKG2A on NK and highly differentiated CD8+ T cells to inhibit immune responses, contributing to senescent cell accumulation. Flow cytometry of senescent fibroblasts, p38 inhibitor experiments, in vitro NK and CD8+ T cell cytotoxicity assays with NKG2A blocking antibody, immunohistochemistry of human skin sections Nature communications High 31160572
2019 HIV-1 Nef protein downregulates HLA-E surface levels by targeting the cytoplasmic tail of HLA-E; cytoplasmic tail swap experiments showed that the HLA-A2 cytoplasmic tail grafted onto HLA-E abolished Nef-mediated downmodulation, demonstrating that Nef acts on the HLA-E cytoplasmic tail specifically. Primary HIV-1 strain infection of CD4+ T cells, single Nef/Vpu protein expression in T cell lines, cytoplasmic tail swap experiments, FACS for surface HLA-E Journal of virology High 31375574
2022 SARS-CoV-2 non-structural protein 13 (Nsp13) encodes a peptide presented by HLA-E that, unlike self-peptides, prevents binding of HLA-E to the inhibitory receptor NKG2A, rendering infected target cells susceptible to NKG2A-expressing NK cell killing; NKG2A+ NK cells are particularly activated in COVID-19 patients and can limit SARS-CoV-2 replication in infected lung epithelial cells. HLA-E peptide loading and NKG2A binding assays, NK cell activation assays, in vitro SARS-CoV-2 replication suppression assays, flow cytometry of NK cells from COVID-19 patients Cell reports High 35235832
2022 Crystal structures and SAXS analysis show that HLA-E-VL9 (canonical leader peptide) complexes are more stable and compact, while HLA-E bound to pathogen-derived non-VL9 peptides adopts larger, more extended conformations in solution with reconfiguration of a key TCR-interacting α2 region; three HLA-E-exclusive residues position VL9 close to the α2 helix and allow non-VL9 peptide binding with an alternative binding motif. X-ray crystallography, small-angle X-ray scattering (SAXS), excess peptide experiments Cell reports High 35705051
2023 HLA-E is largely retained in the ER after synthesis due to limited supply of high-affinity peptides, with its cytoplasmic tail contributing to ER retention; once at the cell surface, HLA-E is unstable and rapidly internalized; the cytoplasmic tail facilitates internalization and enrichment in late and recycling endosomes. Live cell imaging, FRAP, subcellular fractionation, cytoplasmic tail mutant constructs, pulse-chase experiments The Journal of experimental medicine High 37140910
2023 Platelet-derived RGS18 promotes HLA-E expression on circulating tumor cells through AKT-GSK3β-CREB signaling; this HLA-E upregulation enables CTCs to evade NK cell surveillance via the HLA-E:CD94-NKG2A checkpoint axis, facilitating metastasis. Mechanistic studies including RGS18 knockdown/overexpression, AKT-GSK3β-CREB pathway inhibitors, in vitro NK cell killing assays, in vivo mouse metastasis models Cancer cell High 36706761
2023 Among 16 common HLA class I signal peptide variants, only 6 ('functional SPs') are efficiently processed to generate epitopes enabling CD94/NKG2 engagement; the single functional HLA-B SP (HLA-B/-21M) induces high HLA-E expression but confers the lowest receptor recognition, and it competes with other SPs to reduce overall CD94/NKG2A recognition of target cells. Systematic quantitative HLA-E surface expression assays, CD94/NKG2A binding assays, NK cell functional assays, genetic population analysis Nature immunology High 37264229
2023 A yeast-displayed peptide library screen identified 500 unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C; some peptides selectively activate NKG2C+ NK cells; human and CMV proteome-derived HLA-E-presented peptides capable of signaling through both receptors were identified using trained prediction algorithms. Yeast-display peptide library screening, CD94/NKG2A and CD94/NKG2C binding selection, NK cell activation assays Nature communications High 37558657
2015 NKG2A+ NK cell degranulation is inhibited by HLA-E loaded with almost all tested peptides (CMV, Hsp60, HLA class I-derived), whereas NKG2C+ NK cell activation is selectively enhanced only by a restricted set of HLA-E peptide complexes, particularly HLA-E/HLA-G peptide, which also triggers NKG2C receptor internalization. NK cell degranulation (CD107a) assays with HLA-E peptide-loaded target cells, flow cytometry, Bafilomycin experiments for receptor internalization Human immunology High 26382247
2015 HLA-E expression on myeloma cells is substantially upregulated in the bone marrow microenvironment in vivo (compared to in vitro), abrogating degranulation of NKG2A+ NK cell subsets; NKG2A-negative, KIR-ligand-mismatched NK cells show the highest anti-myeloma reactivity. In vivo xenograft mouse model (RAG-2-/- γc-/- mice), ex vivo HLA-E expression analysis, NK cell degranulation assays under hypoxic conditions (0.6% O2) Cancer immunology, immunotherapy High 25920521
2018 HLA-E presents ER-stress-generated signal peptides; bortezomib-induced ER stress in multiple myeloma cells specifically reduces cell surface HLA-E expression (without affecting classical HLA class I), selectively sensitizing myeloma cells to killing by NKG2A single-positive NK cells through loss of NKG2A/HLA-E inhibitory signaling. Bortezomib treatment of MM cells, FACS for surface HLA-E and HLA class I, NK cell subpopulation cytotoxicity assays with NKG2A single-positive NK cells Oncoimmunology High 30713790
2017 HLA-E presents a glycopeptide from the M. tuberculosis protein MPT32 to CD8+ T cells; recognition requires N-terminal O-linked mannosylation of the peptide by a mannosyltransferase encoded by Mtb gene Rv1002c, representing the first post-translationally modified bacterial antigen presented by HLA-E. HLA-E-restricted CD8+ T cell clone identification, MPT32 antigen characterization, Rv1002c mannosyltransferase knockout experiments, T cell recognition assays Scientific reports High 28676677
2021 HLA-E-restricted CD8+ T cells bearing high-affinity TCRs for HLA-E are regulated by inhibitory NK receptors KIR2DL1 and KIR2DL2/L3, while lower-affinity TCR-bearing T cells express activating NKG2C; KIR2D/HLA-C interaction regulates T cells with high self-reactive TCR affinities, providing self/non-self discrimination for HLA-E-restricted responses. RNA sequencing, flow cytometry, TCR affinity measurements, KIR blocking experiments, cytokine response assays Science immunology High 33893172
2015 Regulation of monocyte-to-macrophage differentiation causes HLA-E upregulation; in differentiated macrophages, the primary intracellular destination of newly synthesized HLA-E is the autophagy-lysosomal network (colocalizing with LC3 and LAMP1) rather than the cell surface, unlike classical HLA class I molecules. Immunofluorescence confocal microscopy, colocalization with LC3/LAMP1, NK cell cytotoxicity assays with anti-NKG2A blocking, subcellular fractionation in U937, THP1, and PBMC-derived macrophages Journal of leukocyte biology High 26310830
2023 Antigen-specific NK cell memory against HIV-1 and influenza develops via a conserved, epitope-specific mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E; individual memory NK cells validated by single-cell cloning show permanent antigen specificity, and KLRG1, α4β7, and NKG2C mark antigen-specific memory NK cells. Single-cell cloning, complex immunophenotyping, HLA-E-restricted peptide identification, in vitro NK cell memory assays Science immunology High 38064568
2019 HLA-E surface expression is regulated by XPO1 (exportin-1); XPO1 inhibition with selinexor significantly reduces HLA-E surface expression on lymphoma cells and primary CLL cells, selectively increasing activation of NKG2A+ NK cells and enhancing NK cell-mediated cytotoxicity against these target cells. Selinexor treatment of lymphoma cell lines and primary CLL cells, FACS for surface HLA-E, NK cell activation assays (CD107a, IFNγ), ADCC assays Frontiers in oncology High 34926302

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 837 9560253
2000 Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science (New York, N.Y.) 499 10669413
2017 HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nature biotechnology 486 28504668
2019 Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nature communications 415 31160572
2000 HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. European journal of immunology 290 10898498
2002 HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. The Journal of biological chemistry 265 12411439
2023 Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer cell 258 36706761
2002 A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. The Journal of experimental medicine 203 12461076
2008 CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence. The Journal of experimental medicine 190 18332182
2000 Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 185 10784586
2020 The NKG2A-HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research 178 32409305
2008 Structural basis for NKG2A/CD94 recognition of HLA-E. Proceedings of the National Academy of Sciences of the United States of America 176 18448674
1998 Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E. Molecular cell 172 9660937
2001 Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. Journal of immunology (Baltimore, Md. : 1950) 158 11714810
2004 Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine. Journal of immunology (Baltimore, Md. : 1950) 144 15494539
2010 Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. PLoS pathogens 143 20195504
2005 HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells. Antiviral therapy 137 15751767
2003 Analysis of HLA-E expression in human tumors. Immunogenetics 135 12618909
2009 HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation 120 19136889
1997 Population genetic studies of HLA-E: evidence for selection. Human immunology 117 9021407
2008 The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity. Tissue antigens 106 18946929
2013 Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. The Journal of biological chemistry 101 23335510
2022 NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer. Cancer cell 98 36099881
2012 HLA-E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. International journal of cancer 96 21953582
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