天然免疫受体CLRs和TLRs在皮肤DC中协同诱导Th17和Th1免疫反应的机理及在宿主防御中的作用

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.

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。

树突细胞DC广泛地分布在淋巴结、外周组织和粘膜等部位，通过TLR和CLR等天然免疫受体感知真菌、病毒和细菌的入侵，在维持免疫稳态和实施宿主防御中起至关重要的作用。但目前我们对DC活化的分子机制，以及DC与巨噬细胞、上皮细胞等协同调节T细胞免疫的区域特征还缺乏了解。本项目研究了DC细胞中参与调节CLR和TLR信号的多个关键分子，包括SHP-2，MYD88，TRIF，TSC1/mTOR和TRAF1，并比较了皮肤真菌感染和系统性感染的天然免疫和适应性免疫特征；揭示了DC细胞通过整合信号转导、表观遗传和细胞代谢等过程来综合调控细胞因子表达和程序性坏死，启动和维持T细胞免疫的新机制；揭示了真菌的新型"模式分子"SEL1及其受体TLR2/TLR4在真菌感染和皮肤免疫中的重要调节功能。通过这些研究我们主要取得了以下成果：1）鉴定出真菌的新型"模式分子"（PAMP）SEL1，确认了TLR2/TLR4是DC和巨噬细胞中识别SEL1的关键受体；2）发现CLR 和TLR通过接头分子SHP-2和MyD88激活TSC1/mTOR通路来调节DC细胞代谢，特别是糖酵解和氧化磷酸化，控制组蛋白乙酰化来调节细胞死亡，影响T细胞反应和抗真菌免疫的新机制；3）发现TRAF1在DC和巨噬细胞中负调节TLR和CLR信号，抑制Th17反应和嗜中性粒细胞细胞浸润，控制真菌皮肤感染的新功能。这些发现为我们理解天然免疫受体信号激活和DC-T细胞互作的机制，阐明DC细胞整合细胞代谢和表观遗传来精准调控区域特异性T细胞免疫的规律，揭示DC与巨噬细胞、组织上皮细胞协同调节免疫反应的区域性特征提供了理论基础，也为治疗真菌感染、控制自身免疫性疾病提供了新思路。

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