Tuberculosis remains an important clinical problem throughout the world. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), is a facultative intracellular pathogen, residing primarily in macrophages. Protective immunity to tuberculosis depends upon the coordinated response of the cellular immune system. Because CD8+ T cells recognize and destroy target cells infected with intracellular pathogens, the CD8+ T cell response may be important for containment of Mtb and elimination of infected cells. Identification and characterization of human cytotoxic T cells may be essential for the understanding of immunity to tuberculosis, and hence may be required for the development of efficacious vaccines and improved therapeutic strategies. In prior work, we have demonstrated that both classically and non-classically restricted, Mtb-specific responses are present in persons infected with Mtb, have demonstrated that CD8+ T cell preferentially recognize heavily infected DC, have demonstrated that non-classically restricted responses comprise a significant fraction of the overall response, and have demonstrated that the non-classical major histocompatibility molecule HLA-E can present Mtb-derived antigen. This work represented the first description of the use of the HLA-lb molecule HLA-E in the recognition of an intracellular pathogen. As a result, the goal of this continuing application is to further our understanding of this antigen recognition system. An increased understanding of this pathway has important implications for understanding the host-response to Mtb, and possibly for improved vaccine design. Thus, this research proposal is focused on defining the mechanisms by which human CD8+ T cells recognize Mtb infected cells.
AIM 1 : Determine the relationship of HLA-E restricted T cell responses with TB disease status.
AIM 2 : Establish whether or not the Mtb-phagosome is a competent antigen processing organelle AIM 3: Characterize Mtb-reactive alpha beta TCR expressing thymocytes

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048090-10
Application #
8007340
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Parker, Tina M
Project Start
2001-07-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
10
Fiscal Year
2011
Total Cost
$303,733
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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