Mycobacterium tuberculosis (Mtb) is an important human pathogen and the available data demonstrate the importance of CD4 T cells in establishing a response that restricts Mtb growth. In mice, high numbers of IFN-gamma producing Mtb-reactive CD4 T cells are first detectable at day 21 post infection and are maintained thereafter. Even so, these cells are unable to mediate Mtb elimination. We will study the T cell response to Mtb using Mtb-specific CD4 TCR tg mice. The first question that we will address is why it takes 21 days before protective T cell populations are established. We favor the view that antigen presentation during this period does not lead to the generation of protective IFN-gamma producing cells but instead to inhibitory Mtb-specific regulatory T cells. In the third AIM of this proposal we will determine if effector or memory Mtb-specific T cell populations can protect animals from Mtb infection and limit Mtb growth. Taken together our studies will provide a framework for understanding the T cell response to Mtb and they will provide the foundation for the potential exploitation of CD4 T cells in the protection and treatment of Mtb infection. Infection with Mycobacterium tuberculosis accounts for at least 1.5 million deaths per year. The experiments proposed here will answer fundamental questions regarding the adaptive immune response to Mtb infection and our findings should have direct relevance to vaccination and human disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI074248-02
Application #
7492157
Study Section
Special Emphasis Panel (ZRG1-F07-L (20))
Program Officer
Jacobs, Gail G
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$49,646
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Hohl, Tobias M; Rivera, Amariliz; Lipuma, Lauren et al. (2009) Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6:470-81
Gallegos, Alena M; Pamer, Eric G; Glickman, Michael S (2008) Delayed protection by ESAT-6-specific effector CD4+ T cells after airborne M. tuberculosis infection. J Exp Med 205:2359-68