KIR3DS1 is presumed to be an NK cell activation receptor. The gene has many (>40) inhibitory alleles, known as KIR3DL1. Various KIR3DL1 subtypes have been shown to interact directly with HLA-I proteins with the Bw4 public epitope. Regardless of its similarity to KIR3DL1, and its established role in HIV disease, KIR3DS1 has only recently been shown to be expressed on NK cells and no ligand has been described. Toward an understanding of KIR3DS1 ligand binding we developed a reporter system for the engagement of KIR3DS1. We continue to dissect the biochemical basis of the apparent lack of KIR3DS1 binding to HLA-Bw4. KIR3DL1 binds to HLA-Bw4 but the highly related KIR3DS1 does not. Despite the lack of direct evidence for interaction, genetic association studies suggest that carriage of KIR3DS1 and Bw4 provides strong protection from the advancement of HIV disease. We have carried out targeted mutagenesis that defines a critical role for Glycine 138 of KIR3DL1 for maintaining HLA-Bw4 binding. In addition, we are collaborating with a group in the process of solving the crystal structure of KIR3DL1 and testing the role that individual residues play in the interactions between this receptor and HLA-Bw4. Lastly, we continue to dissect the biochemical basis of the apparent lack of KIR3DS1 binding to HLA-Bw4. KIR3DL1 binds to HLA-Bw4 but the highly related KIR3DS1 does not. Despite the lack of direct evidence for interaction, genetic association studies suggest that carriage of KIR3DS1 and Bw4 provides strong protection from the advancement of HIV disease. We have carried out targeted mutagenesis that defines a critical role for Glycine 138 of KIR3DL1 for maintaining HLA-Bw4 binding. In addition, we are collaborating with a group in the process of solving the crystal structure of KIR3DL1 and testing the role that individual residues play in the interactions between this receptor and HLA-Bw4

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010747-06
Application #
8349135
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2011
Total Cost
$98,399
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Pymm, Phillip; Illing, Patricia T; Ramarathinam, Sri H et al. (2017) MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nat Struct Mol Biol 24:387-394
Benoit, Bernice M; Jariwala, Neha; O'Connor, Geraldine et al. (2017) CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214. Arch Dermatol Res 309:11-19
Saunders, Philippa M; Pymm, Phillip; Pietra, Gabriella et al. (2016) Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition. J Exp Med 213:791-807
McCullen, M V; Li, H; Cam, M et al. (2016) Analysis of Ly49 gene transcripts in mature NK cells supports a role for the Pro1 element in gene activation, not gene expression. Genes Immun 17:349-57
Augusto, Danillo G; O'Connor, Geraldine M; Lobo-Alves, Sara C et al. (2015) Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo. Eur J Immunol 45:2052-60
O'Connor, Geraldine M; Vivian, Julian P; Gostick, Emma et al. (2015) Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1. J Virol 89:5213-21
Saunders, Philippa M; Vivian, Julian P; Baschuk, Nikola et al. (2015) The interaction of KIR3DL1*001 with HLA class I molecules is dependent upon molecular microarchitecture within the Bw4 epitope. J Immunol 194:781-789
O'Connor, Geraldine M; Vivian, Julian P; Widjaja, Jacqueline M et al. (2014) Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity. J Immunol 192:2875-84
O'Connor, Geraldine M; McVicar, Daniel (2013) The yin-yang of KIR3DL1/S1: molecular mechanisms and cellular function. Crit Rev Immunol 33:203-18
O'Connor, Geraldine M; Seich Al Basatena, Nafisa-Katrin; Olavarria, Viviana et al. (2012) In contrast to HIV, KIR3DS1 does not influence outcome in HTLV-1 retroviral infection. Hum Immunol 73:783-7

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