Endogenous T cell Tolerance in the Intestinal Mucosa

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

DESCRIPTION (provided by applicant): The induction of peripheral tolerance is critical for deterrence of autoimmunity. Most self-reactive T cells are deleted during development in the thymus. However, this deletion process is not absolute and occasionally some self-reactive T cells can escape to the periphery. These self-reactive cells must then either be deleted or regulated in the periphery to prevent autoimmunity. To study these processes we generated mice where antigen expression can be tightly controlled in the small intestinal epithelial cells or in CD11c+ cells (dendritic cells) by the administration of doxycycline. Our system provides the unique ability to examine the endogenous T cell response to tissue-specific and developmentally regulated self antigen. First, we will determine the effect of developmentally regulated intestine-specific antigen on endogenous CDS T cells. We intend to turn antigen on for various lengths of time and define the requirements to initiate an autoimmune response or tolerance. We will directly test whether antigen encounter is critical for generation T cell tolerance. We next aim to determine the consequences of memory T cell encounter with developmentally regulated antigen. We intend to generate pathogen-specific memory T cells and then turn on antigen, allowing us to directly test if memory T cells can be tolerized. Together, these aims will allow us to closely examine the consequences of exposing T cells to tissue-specific and developmentally regulated antigen at various stages of activation. Thus, the studies described herein will provide key insights into the mechanisms controlling tolerance versus autoimmunity in the intestinal mucosa.