There is a void in our understanding of how CD4 T cell responses are generated and maintained. This proposal is aimed at filling this void, by characterizing how pro- inflammatory cytokines govern the initial virus-specific lymphocyte response after infection and the differentiation of memory cells. The underlying hypothesis of this grant is that inflammatory signals enhance primary and memory T cell development. This will be tested by pursuing three specific aims: 1) to determine how IFN? signals increase the peak CD4 T cell response and memory, 2) to characterize early T cell competition for pro-inflammatory cytokines that affect memory cell differentiation, and 3) to establish the mechanism(s) by which IFN? sustains CD4 T cell responses during chronic virus infection. The proposed experiments address fundamental aspects of CD4 T cell control and memory cell differentiation. Information gleaned from these studies will further investigations directed at understanding CD4 T cell regulation of CD8 T cell memory and B cell memory. The long-range research goals are to eventually identify specific molecular pathways that can be pharmacologically targeted to enhance vaccine-induced T cell memory.

Public Health Relevance

Vaccines protect against infection by increasing the number of pathogen-specific white blood cells. These studies investigate how interferons increase the number of these cells. These experiments will hopefully identify new ways to improve vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074862-06
Application #
8281652
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Ferguson, Stacy E
Project Start
2008-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$290,110
Indirect Cost
$94,090
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hirai-Yuki, Asuka; Hensley, Lucinda; McGivern, David R et al. (2016) MAVS-dependent host species range and pathogenicity of human hepatitis A virus. Science 353:1541-1545
Cook, Kevin D; Whitmire, Jason K (2016) LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8+ T Cell Responses. J Immunol 197:119-27
Cook, Kevin D; Shpargel, Karl B; Starmer, Joshua et al. (2015) T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX. Immunity 43:703-14
Maltez, Vivien I; Tubbs, Alan L; Cook, Kevin D et al. (2015) Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium. Immunity 43:987-97
Cook, Kevin D; Kline, Hannah C; Whitmire, Jason K (2015) NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection. J Leukoc Biol 98:153-62
Misumi, Ichiro; Whitmire, Jason K (2014) IFN-λ exerts opposing effects on T cell responses depending on the chronicity of the virus infection. J Immunol 192:3596-606
Cook, Kevin D; Waggoner, Stephen N; Whitmire, Jason K (2014) NK cells and their ability to modulate T cells during virus infections. Crit Rev Immunol 34:359-88
Misumi, Ichiro; Whitmire, Jason K (2014) B cell depletion curtails CD4+ T cell memory and reduces protection against disseminating virus infection. J Immunol 192:1597-608
Cook, Kevin D; Whitmire, Jason K (2013) The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J Immunol 190:641-9
Misumi, Ichiro; Alirezaei, Mehrdad; Eam, Boreth et al. (2013) Differential T cell responses to residual viral antigen prolong CD4+ T cell contraction following the resolution of infection. J Immunol 191:5655-68

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