Regulation of Th2 differentiation by skin-resident dendritic cells

项目摘要 辅助性T细胞2型（Th 2）免疫调节体液应答，并成为过敏性和自身免疫性疾病的基础 以及保护宿主免受寄生虫感染。因此，了解如何开发、维护 Th 2细胞功能的调节将有利于我们对这些疾病的治疗方法。 在遇到由树突状细胞（DC）呈递的同源抗原时，初始CD 4 T细胞需要几个周期， Th 1、Th 2和Th 17细胞等效应细胞的分化途径，但它们如何决定向 Th 2在体内相对于另一种的分化还不完全清楚。体内的DC由高度 异质性亚群，并提供了两个重要的线索分化的CD 4 T细胞-刺激通过 T细胞受体和细胞因子。我们以前已经证明，CD 301 b（Mgl 2）是特异性表达， 大多数CD 11b +DCs在皮肤真皮以及其他器官中， CD 301 b +DCs在2型免疫后导致Th 2细胞发育严重和选择性缺陷 佐剂如木瓜蛋白酶或明矾，或在用巴西日本圆线虫感染之后。 然而，如何CD 301 b + DC是必需的和/或足够的诱导Th 2分化，以及它们是否也发挥作用， 维持外周器官中Th 2细胞的作用尚不清楚。我们最近培育了Mgl 2-Cre小鼠， 并证实了Cre重组酶在CD 11b + DC中的活性。通过使用Mgl 2-Cre小鼠和Mgl 2-DTR 我们先前制造的小鼠（其中CD 301 b + DC中的白喉毒素受体表达允许其 通过注射白喉毒素进行特异性消融），在本建议中，我们将检查（1）是否直接抗原 CD 301 b + DC的呈递和细胞因子产生是引发Th 2分化所必需的，（2）如果 CD 301 b +DCs足以诱导Th 2细胞，以及（3）CD 301 b +DCs是否以及如何被需要用于Th 2细胞， 维持皮肤中的效应和记忆Th 2细胞。这些方法不仅将深化我们的基本 了解Th 2调节的体内机制，也有助于我们改进我们的策略， 治疗过敏性疾病或开发有效的疫苗。

Project Summary T helper type 2 (Th2) immunity regulates humoral responses and underlies allergic and autoimmune diseases as well as host protection against parasitic infections. Thus, understanding how development, maintenance and function of Th2 cells are regulated would benefit our therapeutic approaches against these diseases. Upon encounter with a cognate antigen presented by dendritic cells (DCs), naive CD4T cells take several differentiation paths to effector cells such as Th1, Th2, and Th17 cells, but how they decide on the path to Th2 differentiation over the other in vivo is incompletely understood. DCs in vivo consist of highly heterogeneous subsets and provide two important cues for differentiation of CD4T cells – stimulation through the T cell receptor and cytokines. We have shown previously that CD301b (Mgl2) is specifically expressed by a majority of CD11b+DCs in the dermis of the skin as well as in other organs, and that depletion of CD301b+DCs results in a severe and selective defect in developing Th2 cells upon immunization with type 2 adjuvants such as papain or alum, or after the infection with a hookworm Nippostrongylus brasiliensis. However, how CD301b+DCs are required and/or sufficient for inducing Th2 differentiation and if they also play a role in maintaining Th2 cells in the peripheral organ are unclear. We recently generated Mgl2-Cre mouse and confirmed Cre recombinase activity in CD11b+DCs. By using the Mgl2-Cre mouse and the Mgl2-DTR mouse that we previously made (in which diphtheria toxin receptor expression in CD301b+DCs allows their specific ablation by injecting diphtheria toxin), in this proposal, we will examine (1) if direct antigen presentation and cytokine production by CD301b+DCs are required for priming Th2 differentiation, (2) if CD301b+DCs are sufficient for inducing Th2 cells, and (3) if and how CD301b+DCs are required for the maintenance of effector and memory Th2 cells in the skin. These approaches will not only deepen our basic understanding of the in vivo mechanism of Th2 regulation, but also help us to improve our strategies for treating allergic diseases or developing effective vaccines.