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

描述(由申请人提供)：T细胞动态平衡对适应性免疫系统对各种新病原体的反应和维持免疫记忆至关重要。在辐射或病毒感染导致T细胞耗尽后，它有助于外周T细胞库的恢复。在肿瘤患者中，化疗或放疗诱导的淋巴细胞减少患者过继T细胞治疗后肿瘤特异性T细胞的动态平衡扩增可能有利于患者控制和消除癌症。在HIV感染者中，体内平衡增殖受损会导致CD4+T细胞严重耗尽，并导致疾病进展为艾滋病。胸腺基质淋巴生成素(TSLP)是一种IL-7-1样细胞因子。我们最近证实，人TSLP强烈激活CD11c+未成熟髓系树突状细胞(TSLP-DC)。TSLP-DC诱导同种异体初始CD4+T细胞增殖，随后分化为炎性TH2细胞。最近，我们发现在没有过敏性炎症的情况下，胸腺和扁桃体上皮细胞表达TSLP，这表明人类TSLP可能具有额外的功能。我们发现，在没有外源性抗原和细胞因子的情况下，TSLP激活的DC可以诱导自体初始CD4+T细胞强劲的动态平衡增殖。这一发现提示，胸腺和外周淋巴组织中的上皮细胞表达的TSLP可能在DC介导的T细胞稳态中起关键作用。本研究的目的是：1)研究自体TSLP激活的树突状细胞对人幼稚的CD4+T细胞的稳态增殖作用；2)阐明TSLP激活的树突状细胞诱导内稳态T细胞增殖的分子机制；3)了解TSLP激活的树突状细胞在同种异体系统中诱导炎性TH2分化，而在自体系统中诱导T细胞的自稳增殖。本研究的目的在于确定DC和hTSLP在调节人类外周T细胞稳态中的作用，这可能为增强对感染性疾病和癌症的免疫应答以及控制自身免疫性疾病提供新的策略。

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.