Affinage

KIR2DS2

Killer cell immunoglobulin-like receptor 2DS2 · UniProt P43631

Length
304 aa
Mass
33.5 kDa
Annotated
2026-04-28
28 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIR2DS2 is an activating natural killer cell receptor that transmits stimulatory signals through DAP12 adaptor association mediated by a critical transmembrane lysine residue (PMID:11169398). Crystal structures reveal that despite 99% extracellular sequence identity with its inhibitory paralog KIR2DL2, KIR2DS2 diverges in HLA-C binding due to Tyr45 displacement, enabling peptide-selective recognition of HLA-C*0102-presented viral helicase peptides from HCV and flaviviruses sufficient to inhibit viral replication (PMID:12668644, PMID:34967442, PMID:28916719). KIR2DS2 also recognizes a β2-microglobulin-independent ligand on cancer cells, and NK cells with high KIR2DS2 expression display enhanced cytotoxicity and antibody-dependent cellular cytotoxicity against malignant targets, though co-expression with the inhibitory paralog KIR2DL2 results in dominance of inhibitory signaling (PMID:28202613, PMID:35768150, PMID:24078689).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 High

    Establishing how KIR2DS2 couples to activating signaling: a natural transmembrane mutant demonstrated that the charged lysine residue is essential for DAP12 association and activating signal transduction, defining the molecular basis of KIR2DS2's stimulatory function.

    Evidence cDNA sequencing of natural variant Mp50.2 with co-transfection and functional killing assays

    PMID:11169398

    Open questions at the time
    • Whether other transmembrane residues contribute to DAP12 coupling beyond the lysine
    • Stoichiometry of the KIR2DS2–DAP12 complex not determined
  2. 2003 High

    Resolving why KIR2DS2 does not bind HLA-Cw3 despite near-identical sequence to inhibitory KIR2DL2: the 2.3 Å crystal structure identified Tyr45 and Gln71 displacements as the structural basis for divergent ligand recognition.

    Evidence X-ray crystallography at 2.3 Å with KIR tetramer binding validation

    PMID:12668644

    Open questions at the time
    • What physiological ligands KIR2DS2 does engage remained unknown at this stage
    • Whether Tyr45 alone is sufficient to abolish HLA-C binding was not tested by mutagenesis
  3. 2004 Medium

    Determining the functional outcome when activating and inhibitory KIR receptors are co-expressed: redirected killing assays showed that simultaneous KIR2DL3 and KIR2DS2 engagement produces an outcome governed by signal balance.

    Evidence KIR2DL3-specific mAb ECM41 in redirected killing assays of NK clones co-expressing both receptors

    PMID:15314042

    Open questions at the time
    • Quantitative parameters (threshold ratios) governing activating vs. inhibitory dominance not defined
    • Downstream signaling integration mechanism not characterized
  4. 2013 High

    Clarifying the epistatic hierarchy between KIR2DS2 and KIR2DL2: KIR2DS2+KIR2DL2− NK cells are C1-reactive, but co-expression of KIR2DL2 overrides KIR2DS2 activation, establishing inhibitory dominance within this paralog pair.

    Evidence Functional assays on NK cell clones from 159 KIR/HLA-genotyped individuals

    PMID:24078689

    Open questions at the time
    • Molecular mechanism of inhibitory signal dominance (e.g., phosphatase recruitment kinetics) not resolved
    • Whether licensing status modulates this dominance hierarchy
  5. 2017 High

    Identifying the first physiological ligand: KIR2DS2 directly recognizes conserved flaviviral RNA helicase peptides presented by HLA-C*0102, sufficient to activate NK cells and inhibit HCV and dengue virus replication, establishing KIR2DS2 as a peptide-selective activating receptor in antiviral immunity.

    Evidence NK activation assays, peptide-HLA binding assays, and viral replication inhibition assays with endogenous antigen presentation

    PMID:28916719

    Open questions at the time
    • In vivo relevance for viral clearance in human infection not established
    • Whether KIR2DS2 discriminates additional non-viral peptides on HLA-C*0102
  6. 2017 High

    Revealing a non-classical ligand on cancer cells: KIR2DS2 recognizes a β2-microglobulin-independent surface molecule on tumor cell lines, broadening its ligand repertoire beyond classical MHC class I.

    Evidence siRNA knockdown of β2-microglobulin, anti-HLA blocking antibodies, KIR2DS2 reporter cell assays, and trogocytosis

    PMID:28202613

    Open questions at the time
    • Molecular identity of the β2-microglobulin-independent tumor ligand unknown
    • Whether this ligand is tumor-specific or also expressed on normal cells
  7. 2022 High

    Structural resolution of peptide-selective recognition: the 2.5 Å KIR2DS2–HLA-C*0102 complex structure showed dual binding orientations and identified Tyr45 and a conserved 'AT' peptide motif as determinants of activating versus inhibitory KIR specificity.

    Evidence X-ray crystallography at 2.5 Å of the receptor–pHLA complex

    PMID:34967442

    Open questions at the time
    • Functional consequences of the two binding orientations for signaling not tested
    • Whether the AT motif is necessary and sufficient for activation not confirmed by alanine scanning in cellular assays
  8. 2022 Medium

    Linking KIR2DS2 surface density to effector function: KIR2DS2high NK cells exhibit enhanced spontaneous cytotoxicity and ADCC, with transcriptomic upregulation of cytotoxicity and FCGR pathways, positioning KIR2DS2 expression level as a determinant of NK cell antitumor potency.

    Evidence Flow cytometry, ADCC assays with rituximab/obinutuzumab, bulk and single-cell RNA-seq

    PMID:35768150

    Open questions at the time
    • Causal mechanism linking KIR2DS2 expression to CD16 upregulation not established
    • Whether KIR2DS2high phenotype is stable or dynamically regulated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the β2-microglobulin-independent tumor ligand, the in vivo significance of peptide-selective recognition for viral clearance, and the mechanism by which KIR2DS2 expression level modulates broader NK effector programs remain unresolved.
  • β2-microglobulin-independent ligand identity unknown
  • No in vivo demonstration of KIR2DS2-dependent viral control in human infection
  • Signaling pathway downstream of DAP12 specific to KIR2DS2 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4
Partners
DAP12HLA-C*0102KIR2DL2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Crystal structure of KIR2DS2 at 2.3 Å resolution revealed subtle displacements of two residues (Tyr45 and Gln71) compared to inhibitory KIR2DL2, explaining why KIR2DS2 does not bind HLA-Cw3 despite 99% extracellular amino acid identity with KIR2DL2. KIR tetramers confirmed KIR2DS2 fails to bind HLA-Cw3. X-ray crystallography (2.3 Å) and KIR tetramer binding assay The Journal of experimental medicine High 12668644
2000 A naturally occurring KIR2DS2 mutant (Mp50.2) bearing six non-conservative mutations in the transmembrane region, including at the charged lysine residue, fails to associate with DAP12 adaptor molecules and cannot transduce activating signals, demonstrating that the transmembrane lysine is essential for DAP12 coupling and NK cell activation. cDNA sequencing, co-transfection assays, functional killing assays European journal of immunology High 11169398
2017 KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases (including HCV, dengue, Zika, yellow fever, Japanese encephalitis) presented by HLA-C*0102 on NK cells, and this recognition is sufficient to inhibit HCV and dengue virus replication in vitro. NK cell activation assays, peptide-HLA binding assays, viral replication inhibition assays with endogenously presented peptides Science immunology High 28916719
2022 Crystal structure of KIR2DS2 bound to HLA-C*0102 at 2.5 Å resolution revealed that KIR2DS2 can bind HLA-C*0102 and HLA-A*1101 in two different orientations, that Tyr45 (versus Phe45 in inhibitory KIRs) distinguishes activating from inhibitory KIR binding modes, and that a conserved 'AT' motif in the peptide mediates recognition and determines peptide specificity. X-ray crystallography (2.5 Å) of KIR2DS2/HLA-C*0102 complex Immunology High 34967442
2017 KIR2DS2 recognizes a β2-microglobulin-independent ligand expressed on cancer cell lines, distinct from classical HLA-C1/C2 ligands. siRNA knockdown of β2-microglobulin (>97% reduction of classical MHC-I) did not abolish KIR2DS2 reporter cell activation, and anti-HLA class I antibodies did not block recognition. Trogocytosis of membrane proteins was observed, indicating formation of KIR2DS2 ligand-specific immunological synapses. siRNA knockdown of β2-microglobulin, antibody blocking, KIR2DS2 reporter cell assay, trogocytosis assay Journal of immunology High 28202613
2013 KIR2DS2+ KIR2DL2− NK cell clones are C1-reactive (HLA-C1 specific activation); however, when KIR2DS2 and KIR2DL2 are co-expressed on the same NK cell, inhibitory signaling via KIR2DL2 overrides activating signaling via KIR2DS2. In contrast, co-expression of KIR2DL1 and KIR2DS2 has an additive enhancing effect on NK cell responses. NK cell clone functional assays, FACS-based cytotoxicity/degranulation assays in cohort of 159 KIR/HLA genotyped individuals Journal of immunology High 24078689
2004 Simultaneous engagement of KIR2DL3 (inhibitory) and KIR2DS2 (activating) in NK cell clones co-expressing both receptors was investigated using redirected killing assays with specific monoclonal antibodies, revealing that the functional outcome depends on the balance of activating and inhibitory signals from these co-expressed receptors. Generation of KIR2DL3-specific mAb (ECM41), redirected killing assays in NK clones co-expressing KIR2DL3 and KIR2DS2 International immunology Medium 15314042
2011 KIR2DS2*005 is a fusion gene arising from unequal crossing over between KIR2DS2 and KIR2DS3 within intron 6, resulting in a protein with the KIR2DS2 ectodomain but KIR2DS3 transmembrane/cytoplasmic regions. The fusion protein is expressed on the surface of NK and T lymphocytes as confirmed by dual monoclonal antibody detection. cDNA sequencing, population genetics, dual mAb surface expression analysis on primary NK and T cells Genes and immunity Medium 21593779
2012 KIR2DS2 was selected evolutionarily to lose recognition of HLA-C (unlike its inhibitory counterpart KIR2DL2/3 which recognizes the C1 epitope), establishing that activating and inhibitory paralogs within the KIR2DL2/KIR2DS2 pair have divergent HLA-C binding capacities due to structural differences. Comparative functional and phylogenetic analysis of KIR2DS2, KIR2DL2, KIR2DL3 specificity and avidity for HLA-C Frontiers in immunology Medium 23189078
2012 KIR2DS2 promoter contains a CpG island (−160 to +26, six cytosine sites) that undergoes hypomethylation correlated with increased KIR2DS2 mRNA expression, and this hypomethylation increases after hematopoietic cell transplantation, suggesting promoter methylation as a regulatory mechanism for KIR2DS2 expression. Sodium bisulfite conversion and sequencing of CpG islands, quantitative RT-PCR for KIR2DS2 mRNA Human immunology Medium 22939905
2014 KIR2DS2+ NK cells exhibit enhanced cytotoxicity against glioblastoma (GBM), retaining higher CD69 and CD16 surface expression and secreting more CD107a, granzyme A, and soluble CD137 upon contact with GBM cells. KIR2DS2+ donor NK cells significantly prolonged survival in GBM xenograft NOD/SCID mice. NK cell-mediated GBM killing was partially dependent on NKG2D ligand expression and partially abrogated by anti-NKG2D antibody blockade. FACS sorting, in vitro cytotoxicity assays, degranulation/activation marker analysis, antibody blockade, NOD/SCID xenograft mouse model Journal of immunology Medium 25381437
2022 NK cells with high KIR2DS2 surface expression have enhanced spontaneous cytotoxicity against malignant B cell lines, liver cancer cell lines, and primary CLL cells. KIR2DS2high NK cells have increased CD16 expression and enhanced antibody-dependent cellular cytotoxicity with rituximab and obinutuzumab. Bulk and single-cell RNA sequencing confirmed upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways in KIR2DS2high cells. Flow cytometry, ADCC functional assays, bulk RNA-seq, novel single-cell RNA-seq technique for KIR2DS2+ identification Journal of immunology Medium 35768150

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3. Frontiers in immunology 92 23189078
2013 Large spectrum of HLA-C recognition by killer Ig-like receptor (KIR)2DL2 and KIR2DL3 and restricted C1 SPECIFICITY of KIR2DS2: dominant impact of KIR2DL2/KIR2DS2 on KIR2D NK cell repertoire formation. Journal of immunology (Baltimore, Md. : 1950) 85 24078689
2017 KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C. Science immunology 79 28916719
2003 Crystal structure of the human natural killer cell activating receptor KIR2DS2 (CD158j). The Journal of experimental medicine 71 12668644
2014 NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Journal of immunology (Baltimore, Md. : 1950) 52 25381437
2009 Killer immunoglobulin-like receptors (KIR2DL2 and/or KIR2DS2) in presence of their ligand (HLA-C1 group) protect against chronic myeloid leukaemia. Tissue antigens 50 19493232
1990 Characteristics of binding of Escherichia coli serotype O157:H7 strain CL-49 to purified intestinal mucin. Infection and immunity 49 1969394
1990 Role of the putative "link" glycopeptide of intestinal mucin in binding of piliated Escherichia coli serotype O157:H7 strain CL-49. Infection and immunity 41 1969395
2007 Influence of KIR gene diversity on the course of HSV-1 infection: resistance to the disease is associated with the absence of KIR2DL2 and KIR2DS2. Tissue antigens 37 17559579
2017 The Activating Human NK Cell Receptor KIR2DS2 Recognizes a β2-Microglobulin-Independent Ligand on Cancer Cells. Journal of immunology (Baltimore, Md. : 1950) 31 28202613
2019 KIR2DS2/KIR2DL2/HLA-C1 Haplotype Is Associated with Alzheimer's Disease: Implication for the Role of Herpesvirus Infections. Journal of Alzheimer's disease : JAD 30 30689576
2011 Expression of activating KIR2DS2 and KIR2DS4 genes after hematopoietic cell transplantation: relevance to cytomegalovirus infection. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 30 21596150
2019 Killer Immunoglobulin-Like Receptor 2DS2 (KIR2DS2), KIR2DL2-HLA-C1, and KIR2DL3 as Genetic Markers for Stratifying the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients. International journal of molecular sciences 20 30696053
2012 The KIR2DS2/DL2 genotype is associated with adult persistent/chronic and relapsed immune thrombocytopenia independently of FCGR3a-158 polymorphisms. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 17 22024796
2009 Lack of killer immunoglobulin-like receptor 2DS2 (KIR2DS2) and KIR2DL2 is associated with poor responses to therapy of recurrent hepatitis C virus in liver transplant recipients. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 17 19877200
2016 KIR2DL2 and KIR2DS2 as genetic markers to the methotrexate response in rheumatoid arthritis patients. Immunopharmacology and immunotoxicology 15 27251940
2011 Molecular characterisation of KIR2DS2*005, a fusion gene associated with a shortened KIR haplotype. Genes and immunity 13 21593779
2004 Isolation of a novel KIR2DL3-specific mAb: comparative analysis of the surface distribution and function of KIR2DL2, KIR2DL3 and KIR2DS2. International immunology 13 15314042
2015 Increased frequencies of the killer immunoglobulin-like receptor genes KIR2DL2 and KIR2DS2 are associated with neuroblastoma. Tissue antigens 12 26202659
2000 Identification and molecular characterization of a natural mutant of the p50.2/KIR2DS2 activating NK receptor that fails to mediate NK cell triggering. European journal of immunology 12 11169398
2022 KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity. Journal of immunology (Baltimore, Md. : 1950) 10 35768150
2022 Activating receptor KIR2DS2 bound to HLA-C1 reveals the novel recognition features of activating receptor. Immunology 9 34967442
2019 A novel antibody combination to identify KIR2DS2high natural killer cells in KIR2DL3/L2/S2 heterozygous donors. HLA 7 30381896
2016 KIR2DS2 as predictor of thrombocytopenia secondary to pegylated interferon-alpha therapy. The pharmacogenomics journal 4 26975229
2010 Expression of KIR2DL3 and KIR2DS2 natural killer receptors in exercise. Bulletin of experimental biology and medicine 2 21165439
2012 KIR2DS2 and KIR2DS4 promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT). Human immunology 1 22939905
2024 KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies. Frontiers in oncology 0 39286025
2021 Characterization of the novel KIR2DS2*022 allele identified in a northern Chinese Han individual. HLA 0 34155832