The bacterial pathogen, Mycobacterium tuberculosis, is responsible for 8 million new cases of tuberculosis and 2.9 million deaths per year, worldwide. The host immune responses necessary for protection against disease are not clearly defined. Cell-mediated immunity is required for protection, and recent work has confirmed a role for both CD4 and CD8 T cells in the immune response to this pathogen. Here, experiments designed to examine the exact nature of the contribution of CD8 T cells to the protective immune response are proposed. We have outlined a strategy for determining the actual function of CD8 T cells, either as cytotoxic T cells or IFN-gamma producing cells, or both, in M. tuberculosis infection. This involves testing for the presence of mycobacterial specific CD8 CTLs in various mice, establishing CTL lines, and testing these lines for protective capacity in vivo. A systematic approach to this problem is proposed, including the use of various alternative target cells and sources for CD8 T cells. As an alternative hypothesis, the role of IFN-gamma produced by CD8 T cells will be examined. Using in vitro methods and immunological complementation in gene-disrupted mice, we will determine the role of CD8 T cells in protection against tuberculosis in mice. These studies on the actual role of CD8 T cells will increase our understanding of the host immune responses necessary for protection against M. tuberculosis. Information obtained from the results of the proposed experiments will be of value in designing new immunization strategies for tuberculosis and may suggest potential pathogenic mechanisms by which mycobacteria evade the necessary immune responses, and unveil possible virulence factors for further study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037859-04
Application #
6169266
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$144,299
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lin, Philana Ling; Flynn, JoAnne L (2015) CD8 T cells and Mycobacterium tuberculosis infection. Semin Immunopathol 37:239-49
Myers, Amy J; Marino, Simeone; Kirschner, Denise E et al. (2013) Inoculation dose of Mycobacterium tuberculosis does not influence priming of T cell responses in lymph nodes. J Immunol 190:4707-16
Lin, Philana Ling; Rutledge, Tara; Green, Angela M et al. (2012) CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques. AIDS Res Hum Retroviruses 28:1693-702
Flynn, J L; Chan, J; Lin, P L (2011) Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal Immunol 4:271-8
Mattila, Joshua T; Diedrich, Collin R; Lin, Philana Ling et al. (2011) Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation. J Immunol 186:3527-37
Russell, David G; Barry 3rd, Clifton E; Flynn, JoAnne L (2010) Tuberculosis: what we don't know can, and does, hurt us. Science 328:852-6
Lin, Philana Ling; Flynn, Joanne L (2010) Understanding latent tuberculosis: a moving target. J Immunol 185:15-22
Einarsdottir, Thorbjorg; Lockhart, Euan; Flynn, JoAnne L (2009) Cytotoxicity and secretion of gamma interferon are carried out by distinct CD8 T cells during Mycobacterium tuberculosis infection. Infect Immun 77:4621-30
Windish, Hillarie Plessner; Lin, P Ling; Mattila, Joshua T et al. (2009) Aberrant TGF-beta signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis. J Leukoc Biol 86:713-25
Nolt, Dawn; Flynn, JoAnne L (2004) Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis. Infect Immun 72:2976-88

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