Regulation of Th2 differentiation by skin-resident dendritic cells

项目摘要 辅助性T细胞2型(Th2)免疫调节体液反应，是变态反应性和自身免疫性疾病的基础 以及防止寄生感染的寄主保护。因此，了解如何开发、维护 而Th2细胞功能的调节将有利于我们针对这些疾病的治疗方法。 当遇到树突状细胞(DC)呈递的同源抗原时，幼稚的CD4T细胞会 Th1、Th2和Th17细胞等效应细胞的分化路径，但它们如何决定 在活体内，Th2相对于另一种细胞的分化还不完全清楚。体内的树突状细胞由高度 异质性亚群并为CD4T细胞分化提供两条重要线索--通过 T细胞受体和细胞因子。我们以前已经证明CD301b(Mgl2)是由 皮肤真皮和其他器官中的大多数CD11b+树突状细胞， CD301b+DC在2型免疫后导致Th2细胞发育的严重和选择性缺陷 佐剂如木瓜酶或明矾，或感染钩虫后的巴西尼波斯特罗线虫。 然而，CD301b+DC如何需要和/或足够诱导Th2分化，以及它们是否也发挥作用 外周器官中Th2细胞的维持作用尚不清楚。我们最近培育了Mgl2-Cre小鼠 证实CD11b+DC具有Cre重组酶活性。通过使用Mgl2-Cre小鼠和Mgl2-DTR 我们之前制作的小鼠(其中白喉毒素受体在CD301b+DC中的表达允许其 通过注射白喉毒素进行特定的消融)，在这个建议中，我们将检查(1)是否有直接抗原 CD301b+DC的提呈和细胞因子的产生是启动Th2分化所必需的，(2)如果 CD301b+DC足以诱导Th2细胞，以及(3)CD301b+DC是否需要以及如何诱导Th2细胞 维持皮肤中的效应器和记忆Th2细胞。这些方法不仅将深化我们的基本 了解Th2调节的体内机制，也有助于我们改进应对策略 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.