There is strong evidence that CD4+CD25+Foxp3+ regulatory T (Treg) cells are generated intrathymically in response to self-peptides. Yet, Treg cells also modify immune responses to infectious agents, and how selfpeptide- specific Treg cells can recognize and modify anti-pathogen immune responses, including B and T cell memory formation, is currently unknown. In preliminary studies we have found that Treg cells that are generated based on their specificity for the influenza virus hemagglutinin when it is expressed as a selfantigen in transgenic mice can modulate immune responses to influenza virus. This project will test the hypothesis that Treg cells that have been generated based on specificity for self-peptides can modulate immune responses to influenza virus following activation by crossreactive viral peptides, by bacterial peptides, or by self-peptides at the site of infection.
Aim 1 will determine how such Treg cell activity impacts anti-influenza virus immunity. The ability of Treg cells to modulate the development of protective antibody responses following influenza virus vaccination, and how their activity can affect virus clearance, anti-viral immunity and the inflammation and tissue damage that are induced by influenza virus infection will be assessed.
Aim 2 will determine how infection can modify the representation and activity of Treg cells. Whether influenza virus infection induces short- or long-term changes in the Treg cell repertoire, and the extent to which Treg cell activation in response to influenza virus infection can alter the immune response to a concurrent or subsequent bacterial infection (or vice versa) will be examined.
Aim 3 will determine how TCR specificity for viral and/or self-peptides can guide Treg cell activity in infected hosts. Whether activation of self-peptide-specific Treg cells by weakly crossreactive viral peptides can modify the immune response to influenza virus infection will be examined, and the ability of self-peptides to activate Treg cells to modify the immune response to influenza virus infection will be assessed. The long-term goal is to determine whether and how Treg cell activity might be modified to enhance vaccination and/or limit the morbidity and mortality caused by influenza virus infection.

Public Health Relevance

Influenza virus infection continues to be a major cause of morbidity and mortality world-wide. These studies will determine how regulatory T cells that the immune system generates to prevent potentially harmful immune responses affect the ability to mount protective immune responses to vaccination and/or the growth of virus and accompanying inflammation and tissue damage that occur during influenza virus infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083022-04
Application #
8377008
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$253,205
Indirect Cost
$57,956
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Y; Jiang, B; Guo, Y et al. (2016) Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. Mucosal Immunol :
Thome, Joseph J C; Bickham, Kara L; Ohmura, Yoshiaki et al. (2016) Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med 22:72-7
Yang, Cheng; Khanniche, Asma; DiSpirito, Joanna R et al. (2016) Transcriptome Signatures Reveal Rapid Induction of Immune-Responsive Genes in Human Memory CD8(+) T Cells. Sci Rep 6:27005
Crosby, Erika J; Clark, Megan; Novais, Fernanda O et al. (2015) Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with Leishmania major. J Immunol 195:3301-10
Zens, Kyra D; Farber, Donna L (2015) Memory CD4 T cells in influenza. Curr Top Microbiol Immunol 386:399-421
Weissler, Katherine A; Garcia, Victoria; Kropf, Elizabeth et al. (2015) Distinct modes of antigen presentation promote the formation, differentiation, and activity of foxp3+ regulatory T cells in vivo. J Immunol 194:3784-97
Yu, Minjun; Owens, David M; Ghosh, Sankar et al. (2015) Conditional PDK1 Ablation Promotes Epidermal and T-Cell-Mediated Dysfunctions Leading to Inflammatory Skin Disease. J Invest Dermatol 135:2688-96
Lee, JangEun; Walsh, Matthew C; Hoehn, Kyle L et al. (2014) Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192:3190-9
Beiting, Daniel P; Peixoto, Lucia; Akopyants, Natalia S et al. (2014) Differential induction of TLR3-dependent innate immune signaling by closely related parasite species. PLoS One 9:e88398
Wolf, Amaya I; Strauman, Maura C; Mozdzanowska, Krystyna et al. (2014) Pneumolysin expression by streptococcus pneumoniae protects colonized mice from influenza virus-induced disease. Virology 462-463:254-65

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