Subversion T Cell Response by A. actinomycetemcomitans

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DESCRIPTION (provided by applicant): Aa is a major pathogen implicated in several forms of periodontal diseases, and non-oral infections. Despite extensive investigation, the exact mechanism of pathogenicity of this microorganism remains obscure, though it is believed that the host mediates much of it. There is evidence that this bacterium uses a number of mechanisms to evade the host response. Recent studies in our laboratory have demonstrated that Aa induces a very potent T cell activation response. While up to two-third of all T cells are activated, they exhibit impaired cytokine expression and the majority undergoes apoptosis. The few T cells that do express cytokines, predominantly express IL-10, which has immunosuppressive effects. Many periodontitis patients fail to mount an effective antibody response against periodontal pathogens. Based on data, we have posited that Aa interferes with antigen-specific T cell response by large-scale antigen nonspecific activation. The activated cells include regulatory T cells that suppress the antigen-specificT cell response. We further posit that the Aa cytotoxins kill the majority of T cells by apoptosis. To investigate our hypothesis, we have proposed Specific Aims to: 1) characterize the cellular and molecular mediators of T cell apoptosis; 2) examine the nature of the suppression induced by regulatory T cells and 3) identify and characterize the functional attributes of Aa-specific T cells found in periodontitis sites. The characterization of Aa-mediated immunosuppression will not only aid in understanding of the mechanism of pathogenicity of this organism, but it may offer additional experimental tools for manipulating the T cell response. There is currently great need for developing immunosuppressive tools for therapy of autoimmune diseases and prevention of graft rejection.