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

描述（由申请人提供）：t细胞稳态对于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。它有助于放射或病毒感染引起的T细胞耗竭后外周血T细胞池的恢复。在癌症患者中，化疗或放疗诱导淋巴细胞减少的癌症患者进行过继性T细胞治疗后，肿瘤特异性T细胞的稳态扩增可能有利于患者控制和消除癌症。在hiv感染的受试者中，体内平衡增殖的损害导致CD4 + T细胞的严重耗竭和艾滋病的疾病进展。胸腺基质淋巴生成素（TSLP）是一种类似il -7-1的细胞因子。我们最近证明，人类TSLP强烈激活CD11c+未成熟髓系dc （TSLP- dc）。tslp - dc诱导强烈的同种异体初始CD4+ T细胞增殖并随后分化为炎性TH2细胞。最近，我们发现在没有过敏性炎症的情况下，胸腺和扁桃体的上皮细胞表达TSLP，这表明人类TSLP可能具有其他功能。我们发现，在缺乏外源抗原和细胞因子的情况下，TSLP激活的dc可以诱导自身初始CD4+ T细胞的稳态增殖。这一发现表明，胸腺上皮细胞和外周淋巴组织表达的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：i)表征自体tslp激活的dc诱导的人初始CD4+ T细胞的稳态增殖；ii)阐明tslp激活的dc诱导稳态T细胞增殖能力的分子机制；iii)了解为什么tslp激活的dc在异体系统中诱导炎性TH2分化，而在自体系统中诱导稳态T细胞增殖。本文的具体目的是确定dc和hTSLP在调节人类外周T细胞稳态中的功能，这可能为增强对传染病和癌症的免疫反应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.