T cells have a critical role in regulating the protective immune response to Mycobacterium tuberculosis. As a result of studies supported by AI-27243, our understanding of the interaction between human T cells and macrophages in response to M. Tuberculosis has increased substantially during the last five years. First, M. Tuberculosis antigens activate three major T cell subsets from healthy tuberculin positive donors: V delta2 + gamma delta TCR bearing T cells (gamma delta T cells and CD8+ alpha beta (ab) TCR+ T cells (CD 8 T cells) in addition to CD4+ ab T cell receptor (TCR) bearing T cells (CD 4 T cells. Second, all three T cell subsets produce IFN-gamma and can serve as cytotoxic effector cells (CTL) against M. Tuberculosis infected macrophages, fitting into a Th-1 like pattern. These findings allow refinement of the model in which control of mycobacterial growth and maintenance of immunity requires the activation not only of CD4+ T cells and gamma delta T cells, but also of CD8+ T cells. This model postulates that there is a defined sequence of T cell subset recruitment and that the antigen processing mechanisms used by M. Tuberculosis infected mononuclear phagocytes are critical in the recruitment of T cell subsets and in determining the antigen repertoire recognized by CD4+, CD8+ and gamma delta T cells. In addition, the model postulates that both secretion of macrophage activating cytokines and CTL effector function are necessary for protective immune responses to M. Tuberculosis. There are three specific aims to test the postulates of this model: 1. To further characterize a 10-14KD M. tuberculosis antigen for V delta2+ gamma delta T cells, to determine if the antigen can be detected on the surface of mononuclear phagocytes for presentation to V delta2+ gamma delta T cells and to determine if gamma delta T cells activated by this antigen enhance the production by mononuclear phagocytes of chemokines (MIP-1alpha/beta, RANTES) and cytokines (IL-12, IL-15) that promote T cell recruitment and differentiation into CTL. 2. To characterize the antigen processing pathways of M. tuberculosis antigens for class II MHC presentation to CD4+ T cells, using the 30kD 85B antigen as model antigen. 3. To characterize the repertoire of antigens, the antigen-processing pathway and CTL function of CD8+ T cells reactive to M. tuberculosis in comparison to CD4+ and gamma delta T cells. These studies will provide insight into the regulation of human T cell subsets involved in protective immunity to M. tuberculosis, which is necessary for the design of improved vaccines, and immunotherapies for tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI027243-09
Application #
2003498
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1989-02-01
Project End
2002-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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