Lymphocytes with the gamma delta T cell receptor (TCR) secrete cytokines, chemokines and epithelial cell growth factors, may aid in defense against pathogens, and may help maintain the integrity of the pulmonary epithelium. In AIDS patients, there is selective loss of CD4plus alpha beta T cells (but not gamma delta T cells) resulting in greatly increased susceptibility to Mycobacterium spp. But not to the equally prevalent, closely related, nocardiae. The regulatory interactions between gamma delta T cells and CD4plus alpha beta T cells in response to these pathogens are not known. Our hypothesis is that interactions among subsets of gamma delta T cells and alpha beta T cells differentially regulate lung responses to mycobacterial and nocardial glycolipds that have different structures. We propose the following specific aims in order to test this hypothesis: 1) Determine pulmonary responses to glycolipids extracted from mycolic acid containing pathogens (i.e. M tuberculosis, M. intracellular, and N. Asteroides). To accomplish this we will utilize flow cytomertry and immunohistochemical methods to determine pulmonary T cell responses and PMN - macrophage recruitment following exposure to specific glycolipids. 2) Determine the interactive role of subsets of gamma delta T cells in response to glycolipids with different mycolic acid structure. Using a FACS, we will separate populations of subsets of T cells expressing specific TCR and do pulmonary reconstitution in appropriate murine hosts (i.e. normal BALB/c; C57/BL, athymic nude; Vgamma1.1 transgenic, or specific cytokine deficient mice) followed by analysis of T cell responses to the specific glycolipid fractions. This will permit either removal or replacement of components of the gamma delta T cell response to these glycolipids from each of the pathogens. These studies will determine the importance of the structure of mycobacterial glycolipids on mechanisms regulating T cell function during pulmonary protection especially as related to AIDS.
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