The overall goal of this proposal is to better understand the functional relevance and development of antigen-specific CD4+ T cell responses in the mouse model of influenza. The ability to potentiate and manipulate CD4+ T cell responses has important implications for immune therapy in infectious diseases, cancer and AIDS. In this study, influenza viruses containing defined CD4+ epitopes on the 1-Ab background inserted in either the hemagglutinin or neuraminadase will be generated using reverse genetics. These viruses will then be used to characterize the development, kinetics, phenotype and effector function of antigen-specific CD4 T cells in primary, secondary and memory phases of the C57BL/6 model of influenza infection using tetramer staining, intracellular cytokine staining and ELISPOT analyses. These data will be used to determine the effector mechanisms of antigen-specific CD4+ T cells in the influenza model. Using a transgenic T cell receptor mouse, the effect of the quantity and quality of CD4+ T cell responses on influenza primary and secondary infection will also be determined. Finally, the effects of antigen-specific vs. unrelated antigen priming by influenza on allergic responses on different genetic backgrounds will be examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI065097-02
Application #
7084639
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Lacourciere, Karen A
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Rutigliano, John A; Sharma, Shalini; Morris, Melissa Y et al. (2014) Highly pathological influenza A virus infection is associated with augmented expression of PD-1 by functionally compromised virus-specific CD8+ T cells. J Virol 88:1636-51
Thomas, Paul G; Handel, Andreas; Doherty, Peter C et al. (2013) Ecological analysis of antigen-specific CTL repertoires defines the relationship between naive and immune T-cell populations. Proc Natl Acad Sci U S A 110:1839-44
Thomas, Paul G; Brown, Scott A; Morris, Melissa Y et al. (2010) Physiological numbers of CD4+ T cells generate weak recall responses following influenza virus challenge. J Immunol 184:1721-7
Moffat, Jessica M; Handel, Andreas; Doherty, Peter C et al. (2010) Influenza epitope-specific CD8+ T cell avidity, but not cytokine polyfunctionality, can be determined by TCR? clonotype. J Immunol 185:6850-6
Rutigliano, John A; Morris, Melissa Y; Yue, Wen et al. (2010) Protective memory responses are modulated by priming events prior to challenge. J Virol 84:1047-56
La Gruta, Nicole L; Rothwell, William T; Cukalac, Tania et al. (2010) Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest 120:1885-94
Thomas, Paul G; Dash, Pradyot; Aldridge Jr, Jerry R et al. (2009) The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30:566-75
Rutigliano, John A; Doherty, Peter C; Franks, John et al. (2008) Screening monoclonal antibodies for cross-reactivity in the ferret model of influenza infection. J Immunol Methods 336:71-7
Kedzierska, Katherine; Thomas, Paul G; Venturi, Vanessa et al. (2008) Terminal deoxynucleotidyltransferase is required for the establishment of private virus-specific CD8+ TCR repertoires and facilitates optimal CTL responses. J Immunol 181:2556-62
La Gruta, Nicole L; Thomas, Paul G; Webb, Andrew I et al. (2008) Epitope-specific TCRbeta repertoire diversity imparts no functional advantage on the CD8+ T cell response to cognate viral peptides. Proc Natl Acad Sci U S A 105:2034-9

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