皮肤组织是保护机体免受物理、化学因子伤害和病菌入侵的重要免疫组织，具有鲜明的区域免疫特色。皮肤组织驻扎三种树突状细胞，包括朗格汉斯细胞, CD103+ DC 和 CD11b+ DC，它们通过CLR和TLR等天然免疫受体识别真菌感染，介导Th17和Th1免疫反应，实施宿主防御。我们的前期工作发现了在CLR和TLR信号通路中起正调节作用的SHP-2、MyD88和起负调节的作用的TRAF1，并构建了在DC中特异性敲除这些分子，引起CLR和TLR信号失活或上调的小鼠模型。本项目拟利用这些独特的小鼠模型，结合皮肤真菌感染，系统地研究CLR和TLR信号在不同的DC亚群中协同诱导Th17和Th1的分子和细胞学机制，阐明区域免疫反应的基本特征与规律，为预防和治疗真菌感染及自身免疫性皮炎提供新策略。

Skin is an important regional immune tissue critically involved in host defense against pathogens and protecting body from damage by physical and chemical agents. Skin resident DCs are composed of Langerhans cells, CD103+DCs and CD11b+DCs, which recognize specific PAMPs of fungi by CLRs and TLRs, whereby initiate anti-fungal Th17 and Th1 responses. However, skin immune response has to be precisely controlled to avoid autoimmune diseases such as allergy and psoriasis. We have previously identified a variety of signaling molecules, including SHP-2, MyD88 and TRAF1, which are either positively or negatively involved in the regulation of CLR and TLR signaling. By generating mice strains which are deficient of SHP-2 or/and MyD88 in DCs, we were able to study the role of CLR and TLR in anti-fungal Th17 and Th1 responses. We have also obtained TRAF1-deficient mice to study how dysregulated CLR/TLR signaling can exacerbate skin inflammation. In this study, we propose to study: the role of SHP-2-mediated CLR signaling in skin DCs in the regulation of anti-fungal Th17/Th1 responses; how SHP-2-mediated CLR and MyD88-mediated TLR collaborate in the initiation of Th17/Th1 responses after skin fungal infection; the role of TRAF1 in skin fungal infection by controlling the magnitude of CLR/TLR signaling. Thorough these studies, we aim to unravel the mechanisms by which CLR/TLR signaling in distinct skin DC compartments collaborate in the initiation of anti-fungal Th17/Th1 responses, and provide new insight into the development of novel strategies to prevent and treat fungal infection and chronic skin inflammation.