Tuberculosis (TB) kills 2 million people every year. Although most humans control Mtb infection and maintain it in a latent state, ~10% of infected people have active or reactivated TB. It is our hypothesis that the M. tuberculosis infection of the human host results in a mutually beneficial structure, the granuloma, and the balance of host and microbial factors within this microenvironment determines outcome of infection, during both primary tuberculosis and latent infection. The host effector mechanisms that are important in control of TB remain incompletely understood, and the modulation of these responses, as is necessary for a chronic infection to prevent overwhelming pathology, has only begun to be explored. In this application we will concentrate on a specific T cell subset believed to contribute to the control of Mtb infection, the CD8 T cells. We have been studying CD8 T cells in TB for several years, and many questions remain regarding priming, effector functions, regulation and memory responses of these cells. In this application, we will use both mouse and non-human primate models of TB to address specific aspects of CD8 T cells in TB. We hypothesize that CD8 T cell responses are less than optimal, and effector functions, which include cytokine production and cytotoxic activity, are modulated by regulatory mechanisms. Furthermore, the CD8 T cell memory response is not robust upon challenge, and we hypothesize that the inflammatory response in the lungs during early infection or challenge is insufficient to quickly prime or recall a CD8 T cell response. Cumulatively, these studies will enhance our understanding of the host-pathogen interactions within the granuloma, as well as highlight mechanisms that may prevent bacterial clearance, reduce pathology, or improve control of the infection. These studies have relevance to vaccine development, since several TB vaccines that are entering human trials appear not to induce CD8 T cell responses;the relative importance of these responses compared to other cellular responses is unknown.
The specific aims for this renewal are: 1. Determine the important effector functions of CD8 T cells in tuberculosis, and identify factors that modulate changes in these functions over the course of infection 2. Identify factors that regulate CD8 T cell responses during the course of infection 3. Determine whether CD8 T cell memory is initiated, maintained and recalled in the setting of cured or latent tuberculosis, and the factors that contribute to the ineffective memory response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-A (02))
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Parker, Tina M
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University of Pittsburgh
Schools of Medicine
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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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