ZIA BC 010791 (ZIA) | |||
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Title | Effects of genetic polymorphism in MHC, KIR, and related loci on human disease | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Carrington, Mary | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $842,389 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Bone Marrow Transplantation (10.0%) Cancer (100.0%) |
Cervical Cancer (15.0%) Head and Neck (30.0%) Kaposi Sarcoma (20.0%) Leukemia (20.0%) Lung (10.0%) Sarcoma (15.0%) |
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Research Type | |||
Cancer Progression & Metastasis Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
KIR3DS1 was the first KIR to be associated with the outcome of a viral infection, namely, delayed HIV disease progression in patients with certain HLA B alleles. Since then, it has been extensively linked to other viral infections, autoimmune disorders, cancer development/clearance, and transplantation outcomes. Consequently, it has become one of the most studied KIRs. KIR3DS1 is an activating receptor that stimulates cytotoxicity and IFN-gamma production in NK cells. It is encoded in the KIR3DL1/KIR3DS1 gene locus, a unique KIR locus because it encodes for functionally divergent alleles. Remarkably, while sharing >95% homology in their extracellular domain, KIR3DS1 and its inhibitory counterpart KIR3DL1 have different ligand binding profiles. KIR3DL1 has conclusively been shown to bind HLA A and B proteins with a Bw4 motif. However, attempts to identify a KIR3DS1 ligand by various groups have repeatedly failed. The goal of this study was to identify ligands of KIR3DS1 and thus uncover the mechanistic basis for its influence in various human diseases. To this end, in collaboration with Dr. Marcus Altfeld at the Ragon Institute, we employed soluble receptor binding assays and cell-based functional assays to comprehensively screen HLA class I proteins in two biologically relevant conformation states: as HLA class I complexes, which are folded heavy chains bound to B2 microglobulin (B2m) and peptide, and as HLA class I open conformers (OCs), which are HLA class I heavy chains without bound B2m or peptide. We identified that HLA F OCs are high-affinity ligands of KIR3DS1, and also lower affinity ligands of the inhibitory receptors KIR3DL1 and KIR3DL2. We also demonstrated that this interaction is of functional relevance using reporter cell lines, primary KIR3DS1+ NK cells, and primary CD4+ T cells, providing an explanation for the widespread influence of KIR3DS1 in human disease. This newly identified KIR3DS1+HLA-F axis has many similarities to the well-known stress-induced NKG2D-MIC-A/B axis, even in the context of HIV-1 infection. Although it is less well-studied, HLA-F bears unique and distinguishing characteristics that separates it from all other HLA class I genes. In agreement with previous studies, our data show that HLA-F OCs are expressed on the surface of activated CD4+ T cells. Additionally, HIV-1 infection of CD4+ T cells increased transcription of HLA-F but reduced KIR3DS1 ligand expression, particularly in late-infected cells, which might suggest the employment of an immune-evasion strategy, potentially through the downregulation of HLA F by HIV1 accessory proteins, similar to what has been described for HIV1 Nef for HLA A and HLA B and NKG2D ligands including MIC A. KIR3DS1/HLA F interactions between NK cells and pathologically altered target cells would incur the well-known innate function of NK cells to recognize and eliminate target cells expressing ""stressed self"" ligands. This is supported by our in vitro co-culture assay, which showed that NK cells singly expressing KIR3DS1 are more effective at suppressing HIV1 replication in autologous CD4+ T cells as compared to KIR3DS1 negative NK cells. In addition, our data show that KIR3DS1/HLA-F interactions elicit NK cell production of antiviral and pro-inflammatory cytokines such as IFNgamma, TNF, and MIP1Beta, which would have pleiotropic effects on immune responses. Furthermore, KIR3DS1/HLA F interactions between NK cells and activated CD4+ T cells would also suggest a means of NK cell-mediated adaptive immune regulation. Thus, KIR3DS1 recognition of HLA F OCs expressed on activated immune cells and/or infected target cells provides a mechanistic link between KIR3DS1 and HIV1 disease progression, and will also have relevance for the pathogenesis of other infectious diseases, autoimmune disorders, and tumor immune-surveillance. HLA-B*57 is well known to associate with control of HIV, an observation that has largely been attributed to enhanced CD8+ T cell responses t |