Research Project
9310283
? DESCRIPTION (provided by applicant): This application proposes to continue study the immune factors that are important for the pathogenesis of newly characterized Th17 autoreactive T cells. In the previous funding period, we have made significant progress in investigating the mechanisms by which pathogenic Th17 (IL-17+) and Th1 (IFN-y+) autoreactive T cells cause autoimmune disease, and in studying whether the regulation of the pathogenic Th17 response differs from that of the Th1 response. Our studies demonstrated that increased Th17 responses rely on an enhanced d T cell response, raising the question whether manipulation of ?? T cell activation can prevent undesired Th17 responses. In studying factors that lead to ?? T cell activation, we found that adenosine is an important factor in tipping Th1 and Th17 autoreactive T cell generation in autoimmune uveitis (EAU). Adenosine significantly enhances Th17 responses via a pathway in which it enhances ?? T cell activation. Our preliminary results also showed that ?? T cells express greatly increased numbers of type A2 adenosine receptors (A2ARs) after activation and that this allows them to bind large amounts of adenosine; moreover, activated ?? T cells express decreased amounts of ecto-5'-nucleotidase (CD73), an enzyme critically involved in the generation of extracellular adenosine. The hypothesis of this application is that the dual effects of removal of adenosine by activated ?? T cells and the decreased ability of activated ?? T cells to express CD73, which decreases their ability to convert immunostimulatory ATP/AMP to immunosuppressive adenosine, lead to enhanced Th17 responses and autoimmune disease. We will exploit available knockout mice lacking A2ARs and determine whether the proinflammatory effect of ?? T cells on the Th17 response is limited if their ability to bind adenosine is reduced, whether selective A2AR agonists/antagonists can effectively manipulate Th17 responses, whether manipulation of the enzymatic function of CD73 is effective in controlling the Th17 response, and whether adenosine degradation enzyme (ADA) and ADA inhibitors are effective in manipulation of the regulatory activity of ?? T cells and thus Th17 response. The proposed studies will elucidate the molecular and cellular mechanism by which adenosine regulated autoimmune Th1 and Th17 responses. The continuation of this study and the clarification of the pathogenic role of, and relationship between, IFN-y+ and IL-17+ autoreactive T cells in EAU should contribute to our understanding of the mechanism of autoimmune disease pathogenesis.
