CD4 T cells have long been recognized as crucial component of the protective immune response to M. tuberculosis. HIV+ subjects have a greatly increased susceptibility to tuberculosis, and mice deficient in CD4 T cells are impaired in their control of M. tuberculosis infection. It is generally believed that the major effector mechanism of CD4 T cells in tuberculosis is the production of IFN-gamma for activation of macrophages and subsequent killing of intracellular organisms. Although IFN-gamma production is undoubtedly essential to control of this infection, CD4 T cells likely have other roles in the protective response to M. tuberculosis. In a murine model of chronic tuberculosis, depletion of CD4 T cells resulted in fatal reactivation of the infection. However, overall levels of IFN- gamma in the lung were unchanged, and inducible nitric oxide synthase (NOS2) expression and activity were similar to control mice. Thus, the chronic M. tuberculosis infection was not contained in the absence of CD4 T cells, even in the face of wild type levels of IFN-gamma and reactive nitrogen intermediates. These data suggested the presence of CD4 T cell-mediated effector mechanisms in addition to IFN-gamma and activation of RNI production by macrophages. This proposal focuses on identifying the roles that CD4 T cells play in host defense against M. tuberculosis, apart from IFN-gamma production.
Aim 1 focuses on a role for CD4 T cells in maintaining a functioning CD8 T cell response in the lungs.
Aim 2 is an investigation of the role of CD4 T cells in macrophage activation, focusing on known potential components, including the relative importance of IFNgamma, CD40, and NOS2.
Aim 3 focuses on the spatial relationship of T cells and macrophages within the granuloma, and how the loss of CD4 T cells affects this cell-cell interaction. Finally, Aim 4 is a broad approach to identifying previously unknown CD4 T cell- mediated antimycobacterial mechanisms in in vitro and in vivo models, using gene expression technology. This collaborative project takes advantage of the availability of mouse strains and reagents, as well as the Principal Investigators' previous collaborative work and extensive experience in acute and chronic murine models of tuberculosis. The results obtained are relevant to vaccine design and efficacy, as well as to understanding treatment and prevention of tuberculosis in HIV+ (and therefore CD4 T cell deficient) individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050732-04
Application #
6872157
Study Section
Special Emphasis Panel (ZRG1-BM-2 (01))
Program Officer
Sizemore, Christine F
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$460,689
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gideon, Hannah Priyadarshini; Phuah, JiaYao; Myers, Amy J et al. (2015) Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization. PLoS Pathog 11:e1004603
Flynn, JoAnne L; Gideon, Hannah P; Mattila, Joshua T et al. (2015) Immunology studies in non-human primate models of tuberculosis. Immunol Rev 264:60-73
Lin, Philana Ling; Flynn, JoAnne L (2015) CD8 T cells and Mycobacterium tuberculosis infection. Semin Immunopathol 37:239-49
Scanga, Charles A; Flynn, JoAnne L (2014) Modeling tuberculosis in nonhuman primates. Cold Spring Harb Perspect Med 4:a018564
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
Kozakiewicz, Lee; Phuah, Jiayao; Flynn, Joanne et al. (2013) The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. Adv Exp Med Biol 783:225-50
Green, Angela M; Difazio, Robert; Flynn, Joanne L (2013) IFN-? from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol 190:270-7
Kozakiewicz, Lee; Chen, Yong; Xu, Jiayong et al. (2013) B cells regulate neutrophilia during Mycobacterium tuberculosis infection and BCG vaccination by modulating the interleukin-17 response. PLoS Pathog 9:e1003472
Diedrich, Collin R; Mattila, Joshua T; Flynn, JoAnne L (2013) Monocyte-derived IL-5 reduces TNF production by Mycobacterium tuberculosis-specific CD4 T cells during SIV/M. tuberculosis coinfection. J Immunol 190:6320-8
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

Showing the most recent 10 out of 31 publications