II类反式激活因子（CIITA）是MHC II表达的主导开关。我们之前的研究意外发现CIITA突变体（mCIITA）转基因小鼠II类分子表达下调的同时，Th1应答转换为Th2应答；并确认mCIITA作为NLR启动Nod2和炎症小体介导的信号途径上调IL33，继而诱导Th2细胞因子表达。据此，本项目将结合NLR的调控进展提出"CIITA可通过NLRP信号途径调控Th2亚群分化和免疫应答"的假说，拟用转基因动物、ChIPseq等手段探索:⑴mCIITA在胞浆DAMP激发NLR的机理及其激活Th2应答中T-bet/Gata3消长的表观遗传因素;⑵mCIITA通过NLRP3炎症小体调控产生IL-33的机制；作为固有免疫研究前沿，以mCIITA为探针分析Nod2和炎症小体的信号调控特点，有助于就MHC表达、Th1/Th2亚群转换、非感染性炎症、与适应性免疫的关系，及相关研究的临床意义作出探索和评价。

Thanks to the supports of NSFC projects, an unexpected phenomenon that the Th1 response could be inverted to the Th2 response, in addition to the down-regulated MHC class II expression, has been reported in our previous study when C57BL/6 mice were transgenic with mCIITA, a mutated class II transactivator gene. Further study indicated that the CIITA mutant behaved as a member of the NOD-like receptor (NLR) family to activate IL-33 gene via the NLR-initiating signal pathways, which resulted in a skewing production of the Th2-related cytokines. Based on these observations, together on the progresses of the pattern-recognition receptors (PRRs) and the controls of their signaling, this project focuses on four aspects to explore why mCIITA is able to activate the Th2-dominant immune responses. (1) To dissect the structure basis for the differential expression of functions with mCIITA and wtCIITA molecules, and their roles in stimulating NLRs by the cytosolic DAMPs (damage associated molecular patterns). (2) To reveal the epigenetic mechanisms by which the expression of transcriptional factors T-bet and Gata3 is declined and increased respectively to promote the Th2 responses. (3) To explore the pathways by which mCIITA stimulates the production of IL-33 in a big amount via the NLRP3/inflammasome-mediated signal pathway. (4) To understand the functional significance of the mCIITA-controlled regulation of IL-33 that functions as an inner alarmin. In brief, this project aims at the elucidation of the control mechanisms to the Nod2-/inflammasome-mediated signal pathways by using mCIITA as a probe and on their relationship with adoptive immunity: MHC expression and the Th1/Th2 subset transformation. This study is therefore one of the frontiers in innate immunity and would be helpful to understand how DAMP is involved in the non-infectious inflammations, which would lay a basis for the development of approaches to control the relavant clinical diseases.