A critical early step in the host response to invading microorganisms is the presentation of microbial proteins to the immune system. This proposal is designed to investigate the mechanism of viral antigen processing and presentation to T lymphocytes. It is a continuation of our ongoing efforts to understand in molecular terms viral antigen recognition by MHC class I restricted CD8+ T lymphocytes and MHC class II restricted CD4+ T lymphocytes in the mouse using the type A influenza viruses as a model system. The proposal focuses on two areas: the analysis of the contribution of residues within and outside of an antigenic site in the formation of the antigenic moiety recognized by T lymphocytes in an infected cell and the definition of the intracellular compartment(s) in which newly synthesized viral polypeptides are processed and presented to T lymphocytes. The experimental approach employs cloned populations of cytolytic CD8+ and CD4+ T lymphocytes and synthetic minigenes along with mutant viral polypeptides to probe processing and presentation events in the recognition of the influenza hemagglutinin (HA) and nucleocapsid (NP) proteins.
The specific aims of this proposal are: i) to characterize the antigenic moieties in the influenza HA recognized by CD8+ T lymphocytes; ii) to examine the pathway by which newly synthesized influenza virus polypeptides are processed and presented to CD4+ T lymphocytes. This investigation should provide basic information on the immune response to an important human pathogen. In addition, these studies should help to elucidate the molecular mechanisms involved in the formation of antigenic epitopes recognized by T lymphocytes and thereby provide a framework for future vaccine design.

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 #
5R37AI015608-15
Application #
2060248
Study Section
Virology Study Section (VR)
Project Start
1991-09-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Moser, Emily K; Sun, Jie; Kim, Taeg S et al. (2015) IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection. PLoS One 10:e0120169
Moser, Emily K; Hufford, Matthew M; Braciale, Thomas J (2014) Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog 10:e1004315
Yoo, Jae-Kwang; Braciale, Thomas J (2014) IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection. PLoS One 9:e105872
Sun, Jie; Braciale, Thomas J (2013) Role of T cell immunity in recovery from influenza virus infection. Curr Opin Virol 3:425-9
Yoo, Jae-Kwang; Fish, Eleanor N; Braciale, Thomas J (2012) LAPCs promote follicular helper T cell differentiation of Ag-primed CD4+ T cells during respiratory virus infection. J Exp Med 209:1853-67
Sun, Jie; Dodd, Haley; Moser, Emily K et al. (2011) CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12:327-34
Kim, Taeg S; Sun, Jie; Braciale, Thomas J (2011) T cell responses during influenza infection: getting and keeping control. Trends Immunol 32:225-31
Sun, Jie; Cardani, Amber; Sharma, Ashish K et al. (2011) Autocrine regulation of pulmonary inflammation by effector T-cell derived IL-10 during infection with respiratory syncytial virus. PLoS Pathog 7:e1002173
Yoon, Heesik; Kim, Taeg S; Braciale, Thomas J (2010) The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus. PLoS One 5:e15423
Ream, Rebecca M; Sun, Jie; Braciale, Thomas J (2010) Stimulation of naive CD8+ T cells by a variant viral epitope induces activation and enhanced apoptosis. J Immunol 184:2401-9

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