The candidate holds a Ph.D. with an extremely strong commitment to basic science research, and a specific interest in gastrointestinal mucosal immunology. The candidates short-term goals for this fellowship are 1) to become proficient in immunology using biochemical and genetic techniques to investigate mechanistically immune-mediated pathologies;2) to acquire expertise in conceptually and technologically cutting-edge approaches to experimental design that can elucidate the role of human regulatory T cells in intestinal inflammation;3) to develop professional experience in fostering creative and highly interdisciplinary collaborations between experts in immunology, epithelial biology and microbiology;4) to produce sufficient preliminary data and publications that will serve as the basis for a competitive K01 application. The candidate's long-term career goal is to become an independently funded investigator and make meaningful contributions to our knowledge of gastrointestinal mucosal immunology to benefit human health. The overall theme of this project is to understand the mechanisms and requirements by which human regulatory T cells function in the gut mucosa to promote immune homeostasis. Studies implicate Tregs as critical negative regulators of effector T cell responses in both mice and humans. For immune-mediated diseases and immunodeficiencies, Treg dysfunction is associated with disease pathogenesis and morbidity. While experimental data implicate a role for murine Tregs in mucosal homeostasis, insight into the role of human Tregs during intestinal inflammation is not well characterized due to restrictions on experimenting with human subjects and access to relevant tissues. To address this problem, we will utilize a mouse model capable of engrafting human leukocytes to examine the role of Tregs during intestinal inflammation using two experimental T cell-mediated models of intestinal inflammation, anti-CD3-mediated small intestinal enteropathy and TNBS-mediated colonic inflammation. The specific goal of this study is to test the hypotheses: Human Tregs function in a xenobiotic system to suppress human T cell-mediated intestinal inflammation in a TGF-beta and IL-10 dependent manner. The proposed work will be pursued within the context of an intensive and formalized career development program, which will allow the candidate to acquire expertise in both classic and leading edge immunology and cell biological approaches to studying intestinal immune homeostasis. In addition, a diverse group of researchers at Children's Hospital Boston and Harvard Medical School with expertise in immune regulation and mucosal immunology will be established to oversee the candidate's progress. The research environment will provide an intellectually enriching, technically resourceful and collaborative atmosphere that will catalyze the candidate's scientific productivity. At the conclusion of the award period, the candidate will be well positioned as an applicant for an independent K01 award.
A major obstacle in studying human immune cells and their role in the gastrointestinal tract is the inability to experimentally assess their role during inflammation in vivo. The use of mice capable of engrafting human immune cells offers a unique opportunity to study the relevance and mechanisms of human regulatory T cell function in the gut mucosa. Determining the ability of Tregs isolated from genetically distinct patients to promote immune homeostasis in an experimental model of intestinal inflammation has direct clinical significance and therapeutic potential.