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响应各种新病原体和维持免疫记忆至关重要。它有助于在辐射或病毒感染引起的T细胞耗竭后恢复外周T细胞池。在癌症患者中，在由化疗或放疗诱导的淋巴细胞减少性癌症患者中的过继性T细胞疗法后肿瘤特异性T细胞的稳态扩增可能有益于患者控制和消除癌症。在HIV感染的受试者中，稳态增殖的受损导致CD 4 + T细胞的严重耗竭和疾病进展为AIDS。胸腺基质淋巴细胞生成素（Thymic stromal lymphopoietin，TSLP）是一种IL-7样细胞因子。我们最近已经证明，人TSLP强烈激活CD 11 c+未成熟髓样DC（TSLP-DC）。TSLP-DCs诱导强烈的同种异体初始CD 4 + T细胞增殖和随后分化成炎性TH 2细胞。最近，我们发现TSLP在没有过敏性炎症的情况下由胸腺和扁桃体的上皮细胞表达，这表明人TSLP可能具有额外的功能。我们发现TSLP激活的DC可以在不存在外源性抗原和细胞因子的情况下诱导自体幼稚CD 4 + T细胞的稳健的稳态增殖。这一发现表明，TSLP表达的上皮细胞在胸腺和外周淋巴组织中可能发挥关键作用DC介导的T细胞稳态。本发明的目的是：i）表征由自体TSLP活化的DC诱导的人初始CD 4 + T细胞的稳态增殖; ii）阐明TSLP活化的DC诱导稳态T细胞增殖的能力的分子机制;和iii）为了理解TSLP激活的DC在同种异体系统中诱导炎性TH 2分化的原因，而是自体系统中的稳态T细胞增殖。确定DCs和hTSLP在调节人外周T细胞稳态中的功能的具体目标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.