Natural killer (NK) cells are a distinctive population of lymphocytes that serve critical functionsin innate immunity, adaptive immunity and reproduction. Key molecular elements in the development, education and effector responses of human NK cells are the interactions between HLA class I molecules and both inhibitory and activating NK cell receptors. The conserved interactions of HLA-E with CD94:NKG2 are complemented by the extraordinarily variable interactions of HLA-A, -B and -C with the killer-cell immunoglobulin-like receptors (KIR), polymorphic ligands and receptors that segregate independently. The combination of HLA class I and KIR genotype uniquely diversifies human immune systems and as a consequence is strongly associated with infectious, allergic, autoimmune and inflammatory diseases as well as with reproductive success and the outcome of clinical transplantation. Many of these associations are with the functionally and genetically distinctive A and B groups of KIR haplotypes that are unique to the human species. Because of the manner by which humans migrated out-of-Africa to colonize the other continents of the world, the genetic diversity of present-day human populations varies over a wide range and involves different subsets of KIR and HLA class I variants. Equally varied is their history of exposure to pathogens. Through the development of new methods for the acquisition of sequence data and its automated analysis, the research proposed in Aim 1 will lead to a complete description of the KIR and HLA class I genes and alleles in human populations worldwide. These data will be analysed to determine how the KIR receptors and HLA ligands have co-evolved in each population and how this differs from one population to another.
Aim 2 will investigate a uniquely human KIR gene that emerged early in human evolution, was important in the development of both the KIR A and B haplotypes, but was abruptly inactivated through a single nucleotide insertion. The functionality of this gene will be brought back to life and studied.
Aim 3 will develop new high throughput methods that will investigate how the sequences of the peptides bound by HLA class I modulate the interactions with KIR. The initial focus for the application of these methods will be KIR3DL2 recognition of HLA-A*03 and HLA-A*11.

Public Health Relevance

Natural killer cells directly combat infection and disease and also contribute to reproductive success by remodeling blood vessels of the mother that will nourish the fetus. The NK cells use variable sets of interacting proteins that are specified by dedicated regions of the human genome. This project will examine the variability of these genes in the human population and determine how these differences affect the function of NK cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017892-37
Application #
9392878
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Lapham, Cheryl K
Project Start
1981-05-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
37
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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
Hilton, Hugo G; Parham, Peter (2017) Missing or altered self: human NK cell receptors that recognize HLA-C. Immunogenetics 69:567-579
Robinson, James; Guethlein, Lisbeth A; Cereb, Nezih et al. (2017) Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles. PLoS Genet 13:e1006862
Wu, Shuang; Majeed, Sophia R; Evans, Timothy M et al. (2016) Clathrin light chains' role in selective endocytosis influences antibody isotype switching. Proc Natl Acad Sci U S A 113:9816-21
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:
Ashouri, E; Norman, P J; Guethlein, L A et al. (2016) HLA class I variation in Iranian Lur and Kurd populations: high haplotype and allotype diversity with an abundance of KIR ligands. HLA 88:87-99
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2016) Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. Am J Hum Genet 99:375-91
Alicata, Claudia; Pende, Daniela; Meazza, Raffaella et al. (2016) Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1. Eur J Immunol 46:1511-7
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
Raghavan, Maanasa; Steinr├╝cken, Matthias; Harris, Kelley et al. (2015) POPULATION GENETICS. Genomic evidence for the Pleistocene and recent population history of Native Americans. Science 349:aab3884

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