E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT Abstract A cardinal feature of T lymphocytes is their ability to provide antigen specific immune responses to foreign pathogens while ignoring self-tissues. This self-tolerant state is enforced during T cell development through selection of T cell antigen receptors (TCR) that do not trigger immune responses against self-antigens. The E- protein transcription factors E2A and HEB have been shown to control TCR selection during T cell development. Expression of a self-tolerant TCR leads to activation of the E-protein inhibitor Id3 and consequently suppression of E-protein activities. This regulatory event is both necessary and sufficient for developing T cells passing through selection and reaching maturity. Recent investigations revealed that Id3 deficiency results in acquisition of effector like phenotypes among T cells after TCR selection but prior to stimulation by foreign antigens. This new observation suggests that Id3, in addition to its role in regulating the TCR selection checkpoint, is also needed to prevent premature differentiation from naive T cells into effector and/or memory T cells. One consequence of Id3 disruption in the mouse is development of an autoimmune disorder resembling human Sjogren's syndrome. As in human patients, Id3-/- mice exhibit impaired saliva and tear secretion, lymphocyte infiltration into gland tissues, and pathological damage to salivary and lachrymal glands. How Id3 deletion leads to autoimmune pathology in the gland tissues is not clear. Our recent studies indicate that Id3 controls autoimmunity through regulating the Th2 cytokine IL13. This finding is particularly important since IL13 involvement has been implicated in human patients. Our studies also showed that deletion of Id3 promoted expansion of T helper cells that express IL13. Thus far, little is known about the role of IL13 effector T cells in the development of autoimmunity. Thus, Id3 deficient mouse represents a unique model linking development of IL13 effector T cells with the initiation of an autoimmune disorder. At issue are 1) the underlying mechanism leading to acquisition of the IL13 effector fate and 2) whether premature acquisition of this effector fate among developing T cells plays a direct or indirect role in development of autoimmunity. We propose to further investigate these issues by examining the development and function of IL13 effector T cells in both wild type and Id3 deficient mice. Mechanisms revealed from this study should impact our understanding of Id and E-protein functions in development of IL13 and other parallel effector fates. More importantly, knowledge gained about Id3-mediated regulation of IL13 effectors will provide new strategies for early detection and therapeutic intervention of autoimmune diseases in humans.
The proposed study investigates the role of cytokines and T helper cells in development of autoimmune disorders. The Id3 knockout mouse model used in this study will help provide new strategies for early diagnosis and therapeutic intervention of human Sjogren's syndrome.
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