Controlling vital natural killer (NK) cell functions in immunity and reproduction are variable receptors that recognize polymorphic determinants of major histocompatibility complex (MHC) class I molecules. These ligands and receptors vary greatly between mammalian species, notably between humans and mice, necessitating in-depth analysis of the human system for understanding its basic biology as well as for the development of clinically applicable NK-cell based diagnostics and therapeutics. The human killer-cell immunoglobulin-like receptors (KIR) recognize epitopes of the human MHC class I molecules HLA-A, -B and -C, but it is HLA-C that has evolved to dominate KIR-mediated regulation of human NK cells and it will therefore be the focus for this program of research. Originally described as a bipartite system of two mutually exclusive ligand-receptor pairs, research accomplished over the last six years, with the development and application of more accurate and sensitive methods, points to a greater complexity. KIR polymorphism, HLA-C polymorphism and sequence variability in the peptide bound to MHC-C, are all seen to influence the interactions between KIR and HLA-C, their functional effects, and associations with a wide range of diseases.
Aim 1 will determine how worldwide variation in the five KIR that recognize HLA-C (inhibitory 2DL1, 2DL2 and 2DL3, and activating KIR2DS1 and 2DS4) modulates their strength and specificity for the C1 and C2 epitopes of HLA-C, as well as reactivity with HLA-A and -B.
Aim 3 will employ innovative methodology to define how sequence variation within the many thousands of peptides that can be bound by HLA-C affects the interactions with KIR. Such analysis will assess the relative frequency of permissive and non-permissive bound peptides and determine if certain activating human KIR, notably 2DS2, 2DS3 and 2DS5, which appear unable to bind to HLA-C are in fact highly peptide-specific.
Aim 2 will apply a new form of cytometry, which has much greater resolution and analytical capability than conventional flow cytometry, to examine the heterogeneity of human NK cells and their varied expression of KIR and other receptors. By studying these NK-cell receptor repertoires in cohorts of human blood donors, variation within the human population will be defined and correlated with both KIR and HLA class I genotypes, and their combination. A particular focus for study is to compare the influences on NK- cell receptor repertoire of the KIR A and B haplotypes that have been shown to differentially associate in numerous studies of human disease. These studies of the molecular and cellular variability of NK cells and their receptors should provide insights to the variabilityof the human NK response to infection, cancer, and the allogeneic cells encountered naturally in pregnancy and clinically in tissue and organ transplantation.

Public Health Relevance

Natural killer (NK) cells are a population of white blood cells that provides defense against infection and also contributes to successful reproduction. These functions of NK are controlled by interacting receptors and ligands that exhibit an unusual level of genetic diversity in human populations. This research studies how the genetic diversity alters NK-cell function and contributes to the survival of the human species.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022039-27
Application #
8683056
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Rice, Jeffrey S
Project Start
1985-09-30
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
27
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Hilton, Hugo G; McMurtrey, Curtis P; Han, Alex S et al. (2017) The Intergenic Recombinant HLA-B?46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands. Cell Rep 19:1394-1405
Pugh, Jason L; Nemat-Gorgani, Neda; Norman, Paul J et al. (2017) Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage. J Immunol :
Hilton, Hugo G; Parham, Peter (2017) Missing or altered self: human NK cell receptors that recognize HLA-C. Immunogenetics 69:567-579
Hilton, Hugo G; Blokhuis, Jeroen H; Guethlein, Lisbeth A et al. (2017) Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C. J Immunol 198:1961-1973
Djaoud, Zakia; Guethlein, Lisbeth A; Horowitz, Amir et al. (2017) Two alternate strategies for innate immunity to Epstein-Barr virus: One using NK cells and the other NK cells and ?? T cells. J Exp Med 214:1827-1841
Blokhuis, Jeroen H; Hilton, Hugo G; Guethlein, Lisbeth A et al. (2017) KIR2DS5 allotypes that recognize the C2 epitope of HLA-C are common among Africans and absent from Europeans. Immun Inflamm Dis 5:461-468
Horowitz, Amir; Djaoud, Zakia; Nemat-Gorgani, Neda et al. (2016) Class I HLA haplotypes form two schools that educate NK cells in different ways. Sci Immunol 1:
Hilton, Hugo G; Norman, Paul J; Nemat-Gorgani, Neda et al. (2015) Loss and Gain of Natural Killer Cell Receptor Function in an African Hunter-Gatherer Population. PLoS Genet 11:e1005439
Horowitz, Amir; Guethlein, Lisbeth A; Nemat-Gorgani, Neda et al. (2015) Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation. J Immunol 195:4524-36
Guethlein, Lisbeth A; Norman, Paul J; Hilton, Hugo G et al. (2015) Co-evolution of MHC class I and variable NK cell receptors in placental mammals. Immunol Rev 267:259-82

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