EXCEED THE SPACE PROVIDED. Natural killer (NK) cells are essential mediators of host defence, survival and reproduction. They provide early defence against infection, determine when adaptive immunity is needed, facilitate implantation in pregnancy and kill tumors. To perform these functions NK cells use many receptors, most being differentially expressed to create diversity within NK cell populations. In human and mouse there is striking divergence in the types of NK cell receptor, but a common theme is the engagement of MHC class I or class I-like ligands. The more divergent receptors are also highly polymorphic within mouse and human populations, and particular variants have been associated with resistance to infection. In short there appears to be strong diversifying selection upon the NK cell response, consistent with its role in innate immunity and its potential for terminating infection before incapacitating disease develops. Phylogenetically, humans and mice are quite closely related, indicating that much of the global diversity in NK cell receptor biology remains undiscovered. To determine the overall scope of NK cell receptor diversity we propose to study selected species that represent the phylogenetic range of mammals: the class of species whose defence systems and mode of reproduction are most similar to those of humans. We propose three complementary specific aims that will determine the presence and nature of four types of NK cell receptors in the targeted species: the natural cytotoxicity receptors, the lectin-like receptors encoded by the natural killer complex (NKC), the immunoglobulin-like receptors encoded by the leukocyte receptor complex (LRC) and novel receptors not discovered in the study of humans or mice.
Aim 1 will focus on characterization of cDNA from peripheral blood mononuclear cells, Aim 2 will focus on genes whose expression evaded cDNA analysis, and Aim 3 will focus on genomic organisation of the gene families encoding variable receptors. Rigorous phylogenetic analysis will be used to examine the evolutionary dynamics of individual genes, gene families and entire classes of receptor protein. An accurate phylogenetic history for the NK cell receptor families will be established. Consequently, this investigation will place the seemingly discordant results from humans and mice in their more proper biological context. Understanding how other mammals successfully face infection armed with different NK cell receptors should stimulate development of new strategies and innovative therapies against human infections, particularly zoonoses emerging from other mammalian species. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024258-18
Application #
6828317
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Kirkham, Perry M
Project Start
1991-09-30
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
18
Fiscal Year
2005
Total Cost
$280,000
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Norman, Paul J; Norberg, Steven J; Guethlein, Lisbeth A et al. (2017) Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Genome Res 27:813-823
Wroblewski, Emily E; Guethlein, Lisbeth A; Norman, Paul J et al. (2017) Bonobos Maintain Immune System Diversity with Three Functional Types of MHC-B. J Immunol 198:3480-3493
Guethlein, Lisbeth A; Norman, Paul J; Heijmans, Corinne M C et al. (2017) Two Orangutan Species Have Evolved Different KIR Alleles and Haplotypes. J Immunol 198:3157-3169
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
Abi-Rached, Laurent; Guethlein, Lisbeth A; Norman, Paul J et al. (2015) Chimpanzee susceptibility to hepatitis C virus infection correlates with presence of Pt-KIR3DS2 and Pt-KIR2DL9: paired activating and inhibitory natural killer cell receptors. Immunogenetics 67:625-8
Wroblewski, Emily E; Norman, Paul J; Guethlein, Lisbeth A et al. (2015) Signature Patterns of MHC Diversity in Three Gombe Communities of Wild Chimpanzees Reflect Fitness in Reproduction and Immune Defense against SIVcpz. PLoS Biol 13:e1002144
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
Parham, Peter; Moffett, Ashley (2013) Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol 13:133-44
Hammond, John A; Guethlein, Lisbeth A; Norman, Paul J et al. (2012) Natural selection on marine carnivores elaborated a diverse family of classical MHC class I genes exhibiting haplotypic gene content variation and allelic polymorphism. Immunogenetics 64:915-33
Parham, P; Norman, P J; Abi-Rached, L et al. (2012) Review: Immunogenetics of human placentation. Placenta 33 Suppl:S71-80

Showing the most recent 10 out of 22 publications