T CELLS IN GRANULOMATOUS IMMUNE RESPONSES

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Early immunity to infectious agents generally involves a very well defined T cell response to a few immunodominant epitopes. However, the role of antigen specificity in T cell accumulation at chronic inflammatory sites is much less understood. The primary goal of this application is to understand the role of antigen and T cell receptor specificity in chronic granulomatous inflammatory reactions. This information is not presently available due to the technically challenging problem of tracing the low frequency T cells specific for a given antigen. T cell receptor transgenic animals and their respective antigens will be used to overcome this difficulty. This technology will help us to characterize the phenotype and function of T cells activated specifically by antigen or through alternative activation pathways within a localized inflammatory site. Our model will be one of granulomas induced by Leishmania chagasi donovani (LCD) where T cells are crucial for granuloma formation. T cell receptor transgenic mice with a T cell repertoire consisting only two different monospecific T cells will be infected with recombinant LCD expressing an epitope recognized by only one kind of the T cells. The localization and activation stages of these cells will be measured. The two transgenic T cell populations will be sorted and their capacity to control parasite load, form granulomas, and produce lymphokines will be tested in adoptive transfer studies. The experiments will be repeated in wild type adoptive transfer recipients to examine the function of the monospecific T cells within a normal population. These systems will be used to study the effects of immunization on cytokine and effector functions of specific and non-specific T cells. There are three Specific Aims for our application. First, we will determine the proportion of antigen-specific and unrelated antigen restricted T cells in granulomas and in the immune periphery during infection. (Aim 1). Next, we will study the functional role and characteristics of these defined populations throughout the parasitic infection (Aim 2). Finally, we will use vaccination to modify the T cells, activated specifically by antigen or through alternative activation pathways in the granulomas in order to design new, precisely targeted therapies for T cell functions in parasitic diseases (Aim 3). We believe that the successful completion of this research project will lead to an improved understanding of the role of T cells in granulomatous diseases and thus provide the foundation for new therapeutic methodologies for controlling granulomatous inflammatory diseases, such as leishmaniasis.