T lymphocytes play a central role in almost all immune responses. Their receptors are stimulated by a composite ligand formed by binding of processed fragments of protein antigens to Major Histocompatibility Complex (MHC) glycoproteins. The class I MHC molecules present antigens to T lymphocytes expressing the CD8 glycoprotein and generally of cytotoxic function. In human populations the polymorphic differences between these HLA-A,B,C molecules provide the antigenic target for alloreactive cytotoxic T cells that contribute to rejection of transplanted tissues. The overall goal of this research is to relate the molecular mechanisms of HLA-A,B,C function to their primary and three dimensional structures. A dissection of the interaction of HLA-A,B,C with the CD8 glycoprotein provides one specific aim. A new assay for CD8-class I MHC binding will be used to analyze the natural polymorphism in class I molecules and site. Preliminary results show that HLA-A28 is a natural molecule that does not bind CD8. This unexpected polymorphism will facilitate the proposed analysis and raises questions as to the selective advantage of such a molecule. A major challenge to the rigorous molecular analysis of class I MHC function is the development of biochemical assays for peptide binding and our second specific aim is directed to this goal. Approaches using purified molecules and cells will be investigated. manipulation of beta2-m association is hypothesized as one route to destabilize the structure and increase the availability of the peptide binding site. preparations of class I molecules that are enriched for a chosen peptide will be used to make HLA restricted antibodies. These reagents will be invaluable in studying the intracellular association of class I molecules with peptides. The peptide binding function and central immunological role of HLA- A,B,C has resulted in various pathogens divisively using these molecules. Two examples to be studied under aim 3 are adenovirus which has a protein (E3/19) that traps HLA-A,B,C inside the cell and cytomegalovirus that disguises itself in a coat of beta2-m- microglobulin. By analysis of the mechanisms involved we hope to gain greater insights into HLA-A,B,C function and an understanding of the viral subterfuge.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI017892-14
Application #
2060578
Study Section
Special Emphasis Panel (NSS)
Project Start
1981-05-01
Project End
1999-01-31
Budget Start
1994-05-01
Budget End
1995-01-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
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
Hilton, Hugo G; Guethlein, Lisbeth A; Goyos, Ana et al. (2015) Polymorphic HLA-C Receptors Balance the Functional Characteristics of KIR Haplotypes. J Immunol 195:3160-70
Nemat-Gorgani, Neda; Edinur, Hisham A; Hollenbach, Jill A et al. (2014) KIR diversity in M?ori and Polynesians: populations in which HLA-B is not a significant KIR ligand. Immunogenetics 66:597-611
Kidd, Jeffrey M; Sharpton, Thomas J; Bobo, Dean et al. (2014) Exome capture from saliva produces high quality genomic and metagenomic data. BMC Genomics 15:262
Sanderson, Nicholas D; Norman, Paul J; Guethlein, Lisbeth A et al. (2014) Definition of the cattle killer cell Ig-like receptor gene family: comparison with aurochs and human counterparts. J Immunol 193:6016-30
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2013) Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans. PLoS Genet 9:e1003938
Parham, Peter; Norman, Paul J; Abi-Rached, Laurent et al. (2012) Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules. Philos Trans R Soc Lond B Biol Sci 367:800-11
Parham, Peter; Norman, Paul J; Abi-Rached, Laurent et al. (2011) Variable NK cell receptors exemplified by human KIR3DL1/S1. J Immunol 187:11-9
Parham, Peter; Guethlein, Lisbeth A (2010) Pregnancy immunogenetics: NK cell education in the womb? J Clin Invest 120:3801-4

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