H. PYLORI-SPECIFIC REGULATORY T CELLS THAT LIMIT HOST RESPONSE

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DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and plays an etiologic role in the development of gastritis and peptic ulcer disease. Infection persists for life despite the induction of histologic gastritis and specific immune responses. Similar observations have been made in the H. pylori-mouse model. However, mice lacking either IL-10 or NADPH oxidase develop inflammation in response to H. pylori that is significantly more intense than infected wild type mice, and spontaneously clear the bacteria from the gastric mucosa. Additionally, eradication of H. pylori from immunized mice following challenge is also accompanied by more intense inflammation. Therefore, H. pylori may persist due to the inability of the host to develop sufficiently intense inflammation during infection. The induction of down-regulatory T-cells that prevent aberrant responses to noninvasive bacteria in the colon has been described. These mechanisms may be conserved along the gastrointestinal tract and may be active in the gastric mucosa. This proposal will test the hypothesis that activation of T-cells at the gastric mucosa during H. pylori infection induces IL-10 producing regulatory T cells that suppress the inflammatory response, thus allowing for persistent infection. A correlate of this hypothesis is that vaccination effectively bypasses this down-regulation by activating T-cells in lymphoid tissue where the induction of IL-10 producing T-cells is not favored. We will address this hypothesis by: 1) Characterizing surface markers and cytokine profiles of gastric T cell from infected and immune mice to distinguish regulatory T-cells from protective T-cells. Flow cytometry and ELISA spot assays will be used to examine freshly isolated T-cells. 2) Identify the factors in the gastric mucosa that contribute to the induction of these regulatory cells. Transgenic mice and co-culture models will be used to explore the relationship of specific co-receptors and cytokines to T-cell activation in the stomach. 3) Investigate how regulatory T-cells interact with other cells to down-regulate inflammation. Regulatory T-cells will be studied in mice and in vitro to define the extent of their regulatory properties. These studies will increase our understanding of gastrointestinal immunoregulation and the design of better immunotherapies.