MHC class 1 molecules in immunity against tuberculosis

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DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Pediatric Infectious Diseases. The principal investigator has completed residency training in Pediatrics at the University of Washington and is currently in his final year of fellowship training in Infectious Diseases at the same institution. This program will expand upon his current scientific skills, and promote new skills that will enhance his career development. Specifically, this program promotes the development of a career studying the immune response to tuberculosis. Dr. Michael Bevan will mentor the principal investigator's scientific development. Dr. Bevan is a Professor of Immunology, a Howard Hughes Medical Institute Investigator, and a world-renowned leader in the field of immunology. He has trained numerous postdoctoral fellows and graduate students who themselves have become recognized leaders in their fields. In recognition of this outstanding record, Dr. Bevan received the Excellence in Mentoring Award from The American Association of Immunologists in 2000. To enhance the training, the program will enlist the expertise of Dr. David Sherman, Assistant Professor of Pathobiology. Dr. Sherman is a molecular microbiologist with considerable experience with genetic manipulation of Mycobacterium tuberculosis (Mtb). In addition, an advisory committee of highly regarded scientists will provide scientific and career advice. Research will focus on understanding the roles of CD8+ T cells and MHC class I molecules in immune protection against tuberculosis. To approach these issues, a new system to monitor the activity of T cells specific for Mtb-derived antigens after aerosol infection of mice with M. tuberculosis will be established. This system will enable some of the most fundamental questions in the immunology of tuberculosis to be addressed with greater precision than is possible using currently available tools. The specific aims include: 1) Determining the locations, phenotypes, and functions of CD4+ and CD8+ T cells specific for an Mtb-derived antigen after aerosol infection of mice, 2) Determining the roles of CD4+ vs. CD8+ T cells specific for an Mtb-derived antigen in immunity against tuberculosis, and 3) determining the role of MHC class I molecules in regulating immune processes involved in protection against tuberculosis. In addition to providing important information about tuberculosis, these experiments will shed light on basic immune mechanisms that regulate host defense. The Division of Infectious Disease in the Department of Pediatrics at the University of Washington provides an ideal setting for training physician-scientists by advocating scientific exploration within any laboratory of the university. The training program described in this proposal, which draws on several interdepartmental collaborations, will establish a scientific niche for the principal investigator that will position him uniquely for a successful academic career.