Mature T cells persist within the body for indefinite periods of time, providing protection from a vast array of pathogens. A fraction of naive T cells survive for decades and some memory T cells survive for a lifetime without re-exposure to antigen. It is not known how the lifespan of T cells is regulated at the individual, cellular level or at the population level. Identification of the cellular and molecular interactions regulating the protracted persistence of both naive and memory T cells is essential to understanding T cell homeostasis and immunological memory. The goals of the experiments outlined in this proposal are to identify the molecular mediators of T cell survival downstream of the T cell receptor in naive T cells and determine if memory T cells utilize those same factors. Preliminary data suggest that a survival pathway may exist downstream of TCR:MHC interactions in which TCR signaling modulates expression of Early growth response (Egr) transcription factors and inhibitory DNA binding (Id) proteins (repressers of E protein transcription factors). We will test the hypothesis that interactions between TCR and self-peptide/MHC molecules and/or ligand independent TCR signaling support a gene-expression profile conducive to T cell survival. A new model system will be created to test if the activity of Egr transcription factors support the homeostasis/survival of naive, effector and memory T cells. To this end, a mouse model expressing a T cell specific, dominant-interfering form of Egr in a tetracycline-regulatable fashion will allow the """"""""turn-off of Egr-mediated transactivation at key stages of T cell maturation. The role of Id proteins in the homeostasis and survival of naive, effector and memory T cells will also be examined utilizing Id2-deficient mice. As the expression of Egr and Id molecules is maintained by TCR-derived signals in naive T cells, the role of TCR surface expression and Egr/ld activity in the homeostasis and/or survival of memory T cells will also be examined. Furthermore, the possibility that TCR, interleukin-7-receptor and/or interleukin-15-receptor-mediated signals may synergize in maintaining the memory population will be explored. These studies will improve our understanding of how the immune system recovers following treatment- or illness-induced lymphopenia (such as chemotherapy or HIV infection) and aid in the design of vaccines that provide long-lasting protection from infection. Moreover, by expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells providing possible targets for therapeutic intervention. ? ? ?
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