This proposal is designed to investigate viral antigen recognition by HLA-restricted T lymphocytes and the pathways of viral antigen presentation to T lymphocytes restricted by HLA class I and class II locus products. It is an extension into the human of our ongoing study of immune recognition of the type A influenza viruses. Over the last several years fundamental observations in the field of immunology have opened up new areas of investigation into the structure of antigenic moieties recognized by the antigen receptor on T lymphocytes and the nature of the interaction of antigen and major histocompatibility complex (MHC) gene products. Recently, a major emphasis of our research program has been the analysis of the mechanism of antigen presentation to T lymphocytes where evidence from ours and other laboratories points to major differences in the pathways of antigen presentation to T lymphocytes of different subsets. The examination of these pathways of antigen presentation as well as the definition of antigenic sites on influenza viral polypeptides is the focus of the proposed research. Our class II restricted human T lymphocytes: 1) to characterize influenza virus antigenic moieties which serve as antigenic sites recognized by human T lymphocytes; 2) to examine the antigen presentation events leading to the processing and recognition of influenza polypeptides by human T lymphocytes. Eukaryotic expression vectors will be employed to express influenza genes or fragments of genes in order to identify antigenic sites. Synthetic peptides which mimic these sites will be used to define critical amino acids necessary for binding to class I or class II MHC gene products and/or interaction with T lymphocyte antigen receptors. This investigation should provide basic information on the characteristics of antigenic moieties which are recognized by T lymphocytes directed to this important human pathogen. In addition, these studies should help to elucidate the similarities and differences in the mechanism of antigen presentation to """"""""helper"""""""" and """"""""killer"""""""" T lymphocytes and thereby provide an important framework for future vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028317-04
Application #
3142745
Study Section
Experimental Virology Study Section (EVR)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Varga, Steven M; Braciale, Thomas J (2013) The adaptive immune response to respiratory syncytial virus. Curr Top Microbiol Immunol 372:155-71
Steigerwald-Mullen, P; Kurilla, M G; Braciale, T J (2000) Type 2 cytokines predominate in the human CD4(+) T-lymphocyte response to Epstein-Barr virus nuclear antigen 1. J Virol 74:6748-59
Fan, R; Tykodi, S S; Braciale, T J (2000) Recognition of a sequestered self peptide by influenza virus-specific CD8+ cytolytic T lymphocytes. J Immunol 164:1669-80
Yang, B; Braciale, T J (1995) Characteristics of ATP-dependent peptide transport in isolated microsomes. J Immunol 155:3889-96
Cao, W; Myers-Powell, B A; Braciale, T J (1994) Recognition of an immunoglobulin VH epitope by influenza virus-specific class I major histocompatibility complex-restricted cytolytic T lymphocytes. J Exp Med 179:195-202
Kittlesen, D J; Brown, L R; Braciale, V L et al. (1993) Presentation of newly synthesized glycoproteins to CD4+ T lymphocytes. An analysis using influenza hemagglutinin transport mutants. J Exp Med 177:1021-30
Graham, M B; Dalton, D K; Giltinan, D et al. (1993) Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178:1725-32
Hahn, Y S; Braciale, V L; Braciale, T J (1991) Presentation of viral antigen to class I major histocompatibility complex-restricted cytotoxic T lymphocyte. Recognition of an immunodominant influenza hemagglutinin site by cytotoxic T lymphocyte is independent of the position of the site in the hemagglu J Exp Med 174:733-6
Brown, L R; Nygard, N R; Graham, M B et al. (1991) Recognition of the influenza hemagglutinin by class II MHC-restricted T lymphocytes and antibodies. I. Site definition and implications for antigen presentation and T lymphocyte recognition. J Immunol 147:2677-84
Nygard, N R; Bono, C; Brown, L R et al. (1991) Antibody recognition of an immunogenic influenza hemagglutinin-human leukocyte antigen class II complex. J Exp Med 174:243-51

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