DC-mediated Homeostatic Prolif. of CD4 T Cells by TSLP

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DESCRIPTION (provided by applicant): T-cell homeostasis is critical for the adaptive immune system to respond to a variety of new pathogens and for maintaining immunological memory. It contributes to the recovery of the peripheral T-cell pool after T cell depletion caused by irradiation or viral infection. In cancer patients, homeostatic expansion of tumor-specific T cells following adoptive T cell therapy in lymphopenic cancer patients induced by chemo or radiotherapy may be beneficial for the patients to control and eliminate cancers. In HIV-infected subjects, impairment of homeostatic proliferation causes severe depletion of CD4 + T cells and disease progression to AIDS. Thymic stromal lymphopoietin (TSLP) is an IL-7-1ike cytokine. We have recently demonstrated that human TSLP strongly activated CD11c+ immature myeloid DCs (TSLP-DC). TSLP-DCs induced a strong allogeneic naive CD4+ T cell proliferation and subsequent differentiation into inflammatory TH2 cells. More recently, we found that TSLP was expressed by epithelial cells of thymus and of tonsils in the absence of allergic inflammation, suggesting that human TSLP might have additional functions. We found that TSLP activated DCs could induce a robust homeostatic proliferation of autologous naive CD4+ T cells in the absence of exogenous antigens and cytokines. This finding suggests that TSLP expressed by epithelial cells in thymus and peripheral lymphoid tissues may play a critical role in DC-mediated T cell homeostasis. The objectives of this proposal are: i) to characterize homeostatic proliferation of human naive CD4+ T cells induced by autologous TSLP-activated DCs; ii) to elucidate the molecular mechanisms underlying the ability of TSLP-activated DCs to induce homeostatic T cell proliferation; and iii) to understand why TSLP-activated DCs induce inflammatory TH2 differentiation in the allogeneic system, but homeostatic T cell proliferation in the autologous system. The specific aims in this proposal determining the function of DCs and hTSLP in the regulation of human peripheral T cell homeostasis may provide new strategies in enhancing immune responses to infectious diseases and cancer, and in controlling autoimmune diseases.