Affinage

KIR3DS1

Killer cell immunoglobulin-like receptor 3DS1 · UniProt Q14943

Length
382 aa
Mass
42.5 kDa
Annotated
2026-04-28
42 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIR3DS1 is an activating killer-cell immunoglobulin-like receptor on NK cells that signals through the ITAM-bearing adaptor DAP12 to trigger cytotoxicity, IFN-γ production, and CCL4 secretion upon engagement of its ligand. KIR3DS1 requires DAP12 for surface expression and preferentially recognizes HLA-F open conformers (peptide-free, β2-microglobulin-free forms), which are upregulated on cells infected by HIV, HCV, HAdV, and BK polyomavirus, thereby enabling NK cell-mediated antiviral immunity (PMID:27455421, PMID:30031767, PMID:34533978, PMID:33359499). Loading of HLA-F with peptides—including hemoglobin-derived peptides during HIV infection—abrogates KIR3DS1 binding, providing a potential viral immune-escape mechanism, while rare allotypic variants such as KIR3DS1*014 can additionally bind HLA-Bw4 in a peptide-dependent manner through critical residues at receptor position 138 (PMID:33126487, PMID:21804024, PMID:25740999). The compound genotype of KIR3DS1 with HLA-B Bw4-80Ile is associated with delayed progression to AIDS in HIV-1-infected individuals, consistent with epistatic cooperation between this receptor–ligand pair in antiviral defense (PMID:12134147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Establishing that KIR3DS1 cooperates epistatically with HLA-B Bw4-80Ile to influence HIV-1 disease progression provided the first functional rationale for studying this receptor in antiviral immunity.

    Evidence Genetic epistasis analysis across multiple HIV-1 cohorts

    PMID:12134147

    Open questions at the time
    • No direct molecular interaction between KIR3DS1 and HLA-Bw4 demonstrated
    • Mechanism of protection at the cellular level unresolved
  2. 2007 High

    Demonstrating that KIR3DS1 associates with DAP12 (required for surface expression) and triggers NK cell cytotoxicity and IFN-γ production established its signaling mechanism, while the failure of KIR3DS1-Ig fusions and HLA-Bw4 tetramers to bind indicated that HLA-Bw4 is not a straightforward ligand.

    Evidence Co-IP, cotransfection, functional assays on primary NK cells, soluble fusion protein and tetramer binding assays across broad peptide/HLA panels

    PMID:17202323 PMID:17301953 PMID:17411378 PMID:17641029

    Open questions at the time
    • True physiological ligand unidentified
    • Whether peptide context could enable HLA-Bw4 binding remained untested with comprehensive peptide libraries
  3. 2009 Medium

    Showing that KIR3DS1+ NK cells expand during acute HIV-1 infection in an HLA-B Bw4-80Ile-dependent manner and that KIR3DS1 does not inhibit cytotoxicity against Bw4+ targets reinforced its activating function in vivo while further questioning direct Bw4 recognition.

    Evidence Longitudinal HIV cohort with flow cytometry; NK cell proliferation and cytotoxicity assays against Bw4+/- targets

    PMID:19386717 PMID:19454667

    Open questions at the time
    • Molecular basis for Bw4-80Ile-dependent expansion unclear
    • Indirect genetic association rather than direct binding evidence
  4. 2011 High

    Identifying that the rare KIR3DS1*014 allotype directly binds HLA-Bw4, with position 138 as a key determinant, provided the first direct binding evidence and revealed that allotypic variation dictates ligand specificity.

    Evidence Site-directed mutagenesis and cell-based binding assays with recombinant proteins

    PMID:21804024

    Open questions at the time
    • Binding restricted to a rare allotype; generalizability to common allotypes unclear
    • Structural basis of position 138 contribution unresolved
  5. 2015 High

    Establishing peptide-dependent recognition of HLA-B*57:01 by KIR3DS1 and identifying D0-domain residues (positions 58, 92) critical for ligand binding explained why standard tetramer assays had failed and defined the molecular determinants distinguishing KIR3DS1 from KIR3DL1.

    Evidence Structure-guided peptide binding assays; mutagenesis of D0 domain residues with surface expression and binding readouts

    PMID:25740999 PMID:26109640

    Open questions at the time
    • No crystal structure of KIR3DS1–HLA complex available
    • Full peptide repertoire enabling binding unknown
  6. 2016 High

    The identification of HLA-F open conformers as the primary KIR3DS1 ligand resolved the long-standing ligand question, showing that peptide-free, β2m-free HLA-F drives NK cell degranulation, cytokine production, and HIV replication control.

    Evidence Screening of 100 HLA class I proteins, SPR, biochemical pulldown, primary NK cell functional assays, in vitro HIV inhibition

    PMID:27455421 PMID:27649529

    Open questions at the time
    • Structural basis of KIR3DS1–HLA-F interaction unresolved
    • Relative contribution of HLA-F versus HLA-Bw4 recognition in vivo unclear
  7. 2018 High

    Blocking experiments with KIR3DS1-Fc and anti-HLA-F antibodies on both HLA-null cells and HIV-infected CD4+ T cells established that HLA-F is sufficient to activate KIR3DS1+ NK cells, and extended the axis to HCV infection.

    Evidence Primary NK cell co-culture with HLA-null 721.221 cells and HIV-infected CD4+ T cells; antibody/Fc blocking; HCV cell-culture infection model and humanized mouse model

    PMID:29743316 PMID:30031767 PMID:31270222

    Open questions at the time
    • Contribution of other activating receptors to the observed antiviral effects not fully delineated
    • In vivo relevance in human infection awaits clinical intervention studies
  8. 2020 High

    Demonstrating that peptide loading of HLA-F (particularly with hemoglobin-derived peptides) abrogates KIR3DS1 binding, and that BK polyomavirus infection upregulates HLA-F to activate KIR3DS1+ NK cells, broadened the ligand model to include a peptide-based escape mechanism and a fourth viral context.

    Evidence MS peptidome analysis with recombinant KIR3DS1-Fc binding assays; in vitro BK polyomavirus kidney tubular cell infection with primary NK cell assays and patient biopsy validation

    PMID:33126487 PMID:33359499

    Open questions at the time
    • Peptide-mediated immune escape mechanism demonstrated only in biochemical assays, not in infected-cell cocultures
    • Whether HLA-F peptide loading is actively promoted by viral factors is unknown
  9. 2021 High

    Showing that adenoviral E3/gp19K downregulates HLA-A/B while HLA-F is upregulated on infected organoid cells, enabling KIR3DS1+ NK cell killing, revealed a viral immune-evasion trade-off that exposes infected cells to activating NK receptor surveillance.

    Evidence 3D intestinal organoid HAdV5 infection model, flow cytometry, KIR3DS1+ NK cell killing assays, immunogenetic cohort analysis

    PMID:34533978

    Open questions at the time
    • Whether other viruses that downregulate classical HLA-I similarly expose HLA-F is untested
    • In vivo outcome data linking KIR3DS1 genotype to adenoviral disease severity are limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • No crystal or cryo-EM structure of the KIR3DS1–HLA-F complex exists, leaving the atomic basis of open-conformer selectivity and peptide-mediated escape unresolved; the relative contribution of HLA-F versus HLA-Bw4 recognition to in vivo antiviral protection also remains undefined.
  • No structural model of KIR3DS1–HLA-F interaction
  • In vivo hierarchy of HLA-F versus HLA-Bw4 ligand engagement unknown
  • Whether KIR3DS1 has additional non-HLA ligands is unexplored

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 5 R-HSA-162582 Signal Transduction 4
Partners
HLA-FTYROBP
Complex memberships
KIR3DS1–DAP12 signaling complex

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Genetic epistasis analysis demonstrated that KIR3DS1, in combination with HLA-B alleles encoding isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in HIV-1-infected individuals, suggesting an epistatic interaction between the two loci in NK cell-mediated protection. Genetic epistasis analysis in HIV-1 cohort studies Nature genetics High 12134147
2007 KIR3DS1 associates with the ITAM-bearing adaptor protein DAP12 (demonstrated by cotransfection and coimmunoprecipitation), and its ligation triggers NK cell cytotoxicity and IFN-gamma production. Soluble KIR3DS1-Ig fusion proteins did not bind HLA-Bw4 80I or 80T allotypes on EBV-transformed B cell lines, suggesting HLA-Bw4 ligand recognition may be peptide-dependent. Cotransfection, coimmunoprecipitation, in vitro cytotoxicity assay, cytokine production assay, flow cytometry with soluble fusion proteins Journal of immunology High 17202323
2007 KIR3DS1 surface expression on NK cells is dependent on the adaptor protein DAP12; without DAP12, KIR3DS1 is not expressed on the cell surface. KIR3DS1 is recognized by the antibody Z27 and is expressed on a substantial subset of peripheral NK cells and a small proportion of CD56+ T cells. Transfection, flow cytometry, antibody staining (Z27, DX9), surface expression analysis European journal of immunology High 17202323 17301953
2007 KIR3DS1 ligation by antibody Z27 leads to NK cell IFN-gamma production and degranulation (CD107a expression), confirming activating receptor function on peripheral NK cells. Antibody-mediated ligation, flow cytometry (IFN-gamma, CD107a) Journal of immunology High 17641029
2011 The rare KIR3DS1 allotype KIR3DS1*014 (differing from KIR3DS1*013 at position 138) directly binds HLA-Bw4, providing the first direct evidence of KIR3DS1 binding to HLA-Bw4. Position 138 is a key determinant of ligand specificity, and reactivity is dependent on complex interactions between multiple residues (including positions 199 and 138). Mutagenesis, cell binding assay (flow cytometry with HLA-Bw4-expressing cells), recombinant protein analysis Journal of immunology High 21804024
2015 KIR3DS1 recognition of HLA-B*57:01 is peptide-dependent: specific HIV-derived peptide epitopes presented by HLA-B*57:01 facilitate productive interactions between HLA-B*57:01 and KIR3DS1, while other peptides do not support binding. Structure-driven approach, peptide binding assays, flow cytometry with KIR3DS1-expressing cells and HLA-peptide complexes Journal of virology High 25740999
2015 KIR3DS1-specific polymorphisms at positions 58 and 92 in the D0 extracellular domain, when introduced into KIR3DL1, disrupt surface expression and HLA-Bw4 binding, establishing that these residues are critical for KIR3DS1's distinct ligand binding properties. Mutagenesis, flow cytometry, recombinant protein binding assay, primary NK cell functional assay Journal of immunology High 26109640
2016 KIR3DS1 binds specifically to HLA-F open conformers (peptide-free, beta-2-microglobulin-free forms of HLA-F), but not to peptide-loaded classical HLA class I. Primary KIR3DS1+ NK cells degranulate and produce antiviral cytokines upon encountering HLA-F, and inhibit HIV-1 replication in vitro. HLA-F surface expression is upregulated on activated CD4+ T cells and HIV-infected cells. Screening of 100 HLA class I proteins, biochemical binding assays, surface plasmon resonance, flow cytometry, in vitro HIV replication inhibition assay, primary NK cell functional assays Nature immunology High 27455421
2016 Physical binding of KIR3DS1 (but not KIR3DL1) to HLA-F and other MHC-I open conformers was demonstrated by surface plasmon resonance, biochemical pulldown from cell lines, and heterodimerization with recombinant proteins. KIR3DS1 engagement by surface-bound HLA-F increases granule exocytosis in activated NK cells. Surface plasmon resonance, biochemical pulldown, recombinant protein heterodimerization, granule exocytosis assay PloS one High 27649529
2017 KIR3DS1 mediates activation signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells, but this activation occurs only in Bw4-I80-negative individuals, suggesting HLA-B*51 serves as a KIR3DS1 ligand. KIR3DS1-mediated recognition of HLA-B*51 also plays a role in NK cell education/licensing. NK cell clone functional assays, antibody-mediated blocking, KIR3DS1+ clone killing assays, flow cytometry Frontiers in immunology Medium 28603523
2018 KIR3DS1 binding to HLA-F on HCV-infected cells activates NK cells to control HCV replication in cell culture. HLA-F is upregulated on HCV-infected cells, and the KIR3DS1/HLA-F interaction contributes to NK cell-mediated antiviral response. Cell culture HCV infection model, NK cell activation assays, in vitro viral replication assay, humanized mouse liver model, primary liver tissue analysis Gastroenterology High 30031767
2018 HLA-F on HLA-null 721.221 cells activates primary KIR3DS1+ NK cells to secrete CCL4 and IFN-gamma and express CD107a. Blocking the HLA-F/KIR3DS1 interaction with KIR3DS1-Fc chimeric protein or anti-HLA-F antibodies reduced this activation, establishing HLA-F as sufficient to activate KIR3DS1+ NK cells. Primary NK cell co-culture with HLA-null cell line, antibody-mediated blocking, flow cytometry (CCL4, IFN-gamma, CD107a), exclusive gating strategies Journal of immunology High 29743316
2019 HLA-F on HIV-infected CD4+ T cells activates KIR3DS1+ NK cells to produce CCL4, IFN-gamma, and CD107a. Blocking HLA-F on infected cells with KIR3DS1-Fc chimeric protein or anti-HLA-F monoclonal antibody reduced KIR3DS1+ NK cell activation, demonstrating that the HLA-F/KIR3DS1 interaction is sufficient for NK cell activation against HIV-infected cells. Primary NK cell co-culture with sorted HIV-infected CD4+ T cells, KIR3DS1-Fc blocking, anti-HLA-F antibody blocking, flow cytometry Journal of virology High 31270222
2020 BK polyomavirus infection of kidney tubular cells upregulates surface HLA-F expression, which increases KIR3DS1 binding to infected cells and activates primary KIR3DS1+ NK cells, establishing a mechanism for NK cell recognition of BK polyomavirus-infected cells. In vitro BK polyomavirus infection model, flow cytometry (HLA-F surface expression, KIR3DS1 binding), primary NK cell activation assay, kidney biopsy analysis Kidney international High 33359499
2020 HLA-F loaded with hemoglobin-derived peptides loses affinity for KIR3DS1: peptide-free HLA-F open conformers bind KIR3DS1, but acid elution restoring open conformers rescues binding, while addition of hemoglobin peptide fractions to HLA-F open conformers significantly reduces KIR3DS1 recognition — identifying a mechanism for HIV immune escape via HLA-F peptide loading. Soluble HLA technology, mass spectrometry peptidome analysis, recombinant KIR3DS1-Fc binding assays, K562 cell transfection International journal of molecular sciences Medium 33126487
2021 HLA-F is strongly upregulated on HAdV5-infected intestinal organoid cells, enabling KIR3DS1+ NK cells to kill infected cells more efficiently via the KIR3DS1/HLA-F axis. In contrast, HLA-A and HLA-B are downregulated by adenoviral E3/gp19K, suggesting a viral evasion strategy against CD8+ T cells that simultaneously exposes infected cells to KIR3DS1+ NK cell killing. 3D intestinal organoid infection model, flow cytometry (HLA-F, HLA-A, HLA-B expression), KIR3DS1+ NK cell killing assay, immunogenetic cohort analysis Science immunology High 34533978
2009 KIR3DS1+ NK cells specifically expand during acute HIV-1 infection in the presence of HLA-B Bw480I, demonstrating HLA class I subtype-dependent expansion of KIR3DS1+ NK cells during an acute viral infection. Longitudinal cohort study, flow cytometry, KIR/HLA genotyping Journal of virology Medium 19386717
2009 KIR3DS1 expression on NK cells can be induced after exposure to stimulator cells (221, K562, EBV-B cell lines, B cells), poly(I:C), IL-15, or IL-2. KIR3DS1+ NK cell proliferation and cytotoxicity were not inhibited in a Bw4+ context (unlike KIR3DL1+ NK cells), suggesting KIR3DS1 does not recognize HLA-Bw4 in a physiological context. NK cell stimulation assays, flow cytometry, proliferation assays, cytotoxicity assays with Bw4+/- target cells Journal of immunology Medium 19454667
2007 Despite testing a broad array of Bw4Ile80 HLA class I tetramers with HIV-1-derived peptide epitopes, no tetramer binding to KIR3DS1 expressed on 293-T cells was detected, indicating that HLA-Bw4 with typical CD8+ T cell peptide epitopes does not constitute a KIR3DS1 ligand. Flow cytometry, MHC class I tetramer binding assay, transient transfection of KIR3DS1 on 293-T cells AIDS research and human retroviruses Medium 17411378

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nature genetics 928 12134147
2016 Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nature immunology 190 27455421
2009 HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. Journal of virology 156 19386717
2008 Increased proportion of KIR3DS1 homozygotes in HIV-exposed uninfected individuals. AIDS (London, England) 146 18317000
2007 Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. Journal of immunology (Baltimore, Md. : 1950) 117 17202323
2016 HLA-F and MHC-I Open Conformers Bind Natural Killer Cell Ig-Like Receptor KIR3DS1. PloS one 98 27649529
2008 Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection. Journal of virology 93 18305035
2010 Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation. Blood 83 20124216
2015 Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1. Journal of virology 69 25740999
2005 The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated. European journal of immunology 66 15580659
2013 KIR3DS1/L1 and HLA-Bw4-80I are associated with HIV disease progression among HIV typical progressors and long-term nonprogressors. BMC infectious diseases 63 24059286
2009 Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. Journal of virology 62 19211742
2007 Lack of KIR3DS1 binding to MHC class I Bw4 tetramers in complex with CD8+ T cell epitopes. AIDS research and human retroviruses 60 17411378
2007 Allelic expression patterns of KIR3DS1 and 3DL1 using the Z27 and DX9 antibodies. European journal of immunology 54 17301953
2010 Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing spondylitis. Arthritis and rheumatism 46 20131260
2007 Detection of KIR3DS1 on the cell surface of peripheral blood NK cells facilitates identification of a novel null allele and assessment of KIR3DS1 expression during HIV-1 infection. Journal of immunology (Baltimore, Md. : 1950) 46 17641029
2018 Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture. Gastroenterology 40 30031767
2012 Role of KIR3DS1 in human diseases. Frontiers in immunology 39 23125843
2009 Phenotypic and functional analyses of KIR3DL1+ and KIR3DS1+ NK cell subsets demonstrate differential regulation by Bw4 molecules and induced KIR3DS1 expression on stimulated NK cells. Journal of immunology (Baltimore, Md. : 1950) 31 19454667
2013 Natural killer KIR3DS1 is closely associated with HCV viral clearance and sustained virological response in HIV/HCV patients. PloS one 30 23613999
2011 Analysis of binding of KIR3DS1*014 to HLA suggests distinct evolutionary history of KIR3DS1. Journal of immunology (Baltimore, Md. : 1950) 25 21804024
2017 KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing. Frontiers in immunology 24 28603523
2014 Time to seroconversion in HIV-exposed subjects carrying protective versus non protective KIR3DS1/L1 and HLA-B genotypes. PloS one 21 25330014
2019 HLA-F on Autologous HIV-Infected Cells Activates Primary NK Cells Expressing the Activating Killer Immunoglobulin-Like Receptor KIR3DS1. Journal of virology 20 31270222
2012 Association of KIR3DS1+HLA-B Bw4Ile80 combination with susceptibility to tuberculosis in Lur population of Iran. Iranian journal of immunology : IJI 18 22426166
2018 HLA-F on HLA-Null 721.221 Cells Activates Primary NK Cells Expressing the Activating Killer Ig-like Receptor KIR3DS1. Journal of immunology (Baltimore, Md. : 1950) 15 29743316
2015 KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding. Journal of immunology (Baltimore, Md. : 1950) 13 26109640
2021 KIR3DS1 directs NK cell-mediated protection against human adenovirus infections. Science immunology 12 34533978
2007 A mutation in KIR3DS1 that results in truncation and lack of cell surface expression. Immunogenetics 12 17687550
2010 The profile of KIR3DL1 and KIR3DS1 alleles in an African American population resembles that found in African populations. Tissue antigens 11 20230527
2020 Upregulation of HLA-F expression by BK polyomavirus infection induces immune recognition by KIR3DS1-positive natural killer cells. Kidney international 10 33359499
2008 Investigation of killer cell immunoglobulin-like receptor gene diversity in KIR3DL1 and KIR3DS1 in a transplant population. Tissue antigens 10 18331531
2017 KIR3DS1/HLA-B Bw4-80Ile Genotype Is Correlated with the IFN-α Therapy Response in hepatitis B e antigen-Positive Chronic Hepatitis B. Frontiers in immunology 9 29075265
2014 Protective genotypes in HIV infection reflect superior function of KIR3DS1+ over KIR3DL1+ CD8+ T cells. Immunology and cell biology 8 25112829
2012 In contrast to HIV, KIR3DS1 does not influence outcome in HTLV-1 retroviral infection. Human immunology 8 22609443
2015 Comparison of the KIR3DS1/Bw4 distribution in Chinese healthy and acute myeloid leukemia individuals. Human immunology 6 25636577
2020 The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides. International journal of molecular sciences 4 33126487
2026 Activating KIR3DS1: A key Driver of KIR3DL1/HLA-Bw4-Linked risk in CML. Human immunology 0 42034883
2023 Evaluation of KIR3DL1/KIR3DS1 allelic polymorphisms in Kenyan children with endemic Burkitt lymphoma. PloS one 0 37647275
2018 [The favorable effects of KIR3DS1 and Bw4(80Ile) on viral set point and CD4 count decline in HIV-1 patients with acutely infected with HIV-1 infection]. Zhonghua yi xue za zhi 0 30248785
2014 The KIR3DS1*0130105 allele identified using high-resolution sequence-based typing. Tissue antigens 0 24499056
2014 A novel KIR3DS1*0130107 allele isolated by sequencing from an Asian donor. International journal of immunogenetics 0 24775446