CD4 T cells provide immune defense against Mycobacterium tuberculosis infection. Control of M. tuberculosis infection also requires TNF, IFN-?, iNOS and TLR-mediated innate immune signals. CD4 T cells orchestrate cellular and cytokine-mediated effector mechanisms that inhibit M. tuberculosis growth in the mammalian host. Vaccine induced priming of long-term memory CD4 T cells specific for M. tuberculosis, therefore, is an important but, to date, incompletely met goal. The proposed experiments focus on an important question: Why are CD4 T cells induced by natural infection unable to eliminate M. tuberculosis from the host. We hypothesize that natural infection primes mixed populations of effector and regulatory CD4 T cells that restrict M. tuberculosis growth but do not lead to sterile immunity. To test this hypothesis, we generated T cell receptor transgenic mice specific for ESAT-6, an immunodominant M. tuberculosis antigen, and tracked ESAT-6 specific CD4 T cells during infection. Adoptively transferred, Th1 differentiated ESAT-6 specific CD4 T cells provide protection against aerosol infection, enabling mechanistic studies of CD4 T cell mediated protective immunity.
Our first aim i s to investigate the kinetics of clonal CD4 T cell activation, expansion and contraction at different times during the course of TB infection. These studies will determine whether the inability of clear M. tuberculosis infection results from too few specific T lymphocytes, attrition of specific T cells or loss of T cell effector functions during chronic infection.
Our second aim i s to determine which CD4 T cell effector functions are required for protective immunity. These experiments will determine whether IFN-3 and/or TNF production by TB-specific CD4 T cells are essential for protection, and will determine the impact of innate immune responses on activation and differentiation of ESAT-6-specific T cells.
Our final aim i s to identify approaches that optimize in vivo, CD4 T cell-mediated protection. We will induce migration of CD4 T cells to lung parenchyma and airways, optimize in vivo differentiation of ESAT-6 specific CD4 T cells and determine the contribution of Th17 CD4 T cells to protective immunity. These studies will provide unprecedented views of CD4 T cell responses to M. tuberculosis infection and will likely suggest new and practical approaches to optimize immunity against this pathogen.

Public Health Relevance

Vaccines against Tuberculosis, one of the most important and difficult infectious diseases confronting mankind, are only partially effective. Our understanding of immune defense against Mycobacterium tuberculosis, in particular the role of T lymphocytes, is far from complete. The studies proposed in this grant application will determine the major mechanisms that CD4 T cells use to control Tuberculosis. Using a novel mouse strain that was developed in our laboratory, we will discover new approaches to optimize immune clearance of M. tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080619-05
Application #
8484339
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Jacobs, Gail G
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$437,385
Indirect Cost
$207,061
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Gallegos, Alena M; Xiong, Huizhong; Leiner, Ingrid M et al. (2016) Control of T cell antigen reactivity via programmed TCR downregulation. Nat Immunol 17:379-86
Samstein, Miriam; Schreiber, Heidi A; Leiner, Ingrid M et al. (2013) Essential yet limited role for CCR2⁺ inflammatory monocytes during Mycobacterium tuberculosis-specific T cell priming. Elife 2:e01086
Kinnebrew, Melissa A; Buffie, Charlie G; Diehl, Gretchen E et al. (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36:276-87
Shi, Chao; Jia, Ting; Mendez-Ferrer, Simon et al. (2011) Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity 34:590-601
Shi, Chao; Hohl, Tobias M; Leiner, Ingrid et al. (2011) Ly6G+ neutrophils are dispensable for defense against systemic Listeria monocytogenes infection. J Immunol 187:5293-8
Gallegos, Alena M; van Heijst, Jeroen W J; Samstein, Miriam et al. (2011) A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis infection in vivo. PLoS Pathog 7:e1002052
Barkan, Daniel; Stallings, Christina L; Glickman, Michael S (2011) An improved counterselectable marker system for mycobacterial recombination using galK and 2-deoxy-galactose. Gene 470:31-6
Littman, Dan R; Pamer, Eric G (2011) Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10:311-23
Jarchum, Irene; Pamer, Eric G (2011) Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol 23:353-60
Sklar, Joseph G; Makinoshima, Hideki; Schneider, Jessica S et al. (2010) M. tuberculosis intramembrane protease Rip1 controls transcription through three anti-sigma factor substrates. Mol Microbiol 77:605-17

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