The developmental processes governing the generation and control of the intestinal mucosal immune system are, in part, distinct from those involved in development of the peripheral immune system. Understanding these processes is important, since the mucosal immune system is comprised of inductive and effector sites which are critically involved in generation of immunity to tumors, pathogens and vaccines. Moreover, control of intestinal inflammation is requisite for prevention of autoimmunity. The intestinal mucosa has been proposed to be a T cell generative organ but the mechanisms by which T cells may be produced outside of the thymus remain unclear. Therefore, this proposal is centered around developing and utilizing novel model systems to define the requirements for intestinal TCRalphabeta and TCRgammadelta cell development.
The specific aims of this proposal are:
Aim 1. To define the contribution of tissue-specific IL-7 expression to extrathymic T cell development. In mice lacking IL-7 or IL-7 receptor (IL-7R), there is a complete absence of mature TCRgammadelta calls in peripheral and mucosal tissues. In this aim we will characterize TCRgammadelta and TCRalphabeta cell development in mice expressing IL-7 under control of site-specific promoters or in mice grafted with tissues expressing IL-7.
Aim 2. To determine the role of extrathymic IL-7 in TCRgammadelta cell survival and expansion. To determine the site at which IL-7 is important for TCRgammadelta cell expansion/survival we will generate chimeric and transgenic mice expressing TCRgammadelta transgenes and which lack IL-7- /- or which express IL-7 in thymus or intestine.
Aim 3. To determine the requirements for extrathymic positive selection of TCRalphabeta T cells. Our preliminary results indicate that CD8+ TCRalphabeta IEL expressing a transgenic TCR can develop and undergo positive selection in the absence of a thymus. Chimeric mice and bone grafting will be used to determine the requirements for extrathymic positive selection. Transgenic mice with intestine-specific expression of MHC class I will be used to test whether intestinal epithelium can positively select TCRalphabeta T cells. Overall, these studies will provide basic answers to how T call development occurs in general and provide insight into the development and function of the mucosal immune system.
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