GATA3通过ILC2细胞调控CD4+ T细胞分化可塑性致胰岛自身免疫启动的机制研究

机体失去胰岛自身抗原免疫耐受是导致1型糖尿病(T1DM)发生的机制。失去免疫耐受的原因涉及遗传因素和环境因素，具体机制尚无定论。本课题组于2017年发现GATA3为中国汉族人群易感基因，GATA3是二型天然淋巴细胞ILC2及Th2的关键转录因子，ILC2调控多种CD4+T细胞的功能。因此，我们假设：免疫失衡时，GATA3基因多态性影响其在ILC2中的表达量,改变ILC2的细胞因子分泌谱，进而导致CD4+T细胞极化偏移，失去免疫耐受，最终启动自身免疫反应。我们拟利用过继性转移BDC2.5T细胞的动物模型进行体内实验及人PBMC进行体外实验，以病原体诱导机体免疫应激,探讨应激情况下，ILC2细胞中GATA3的基因多态性与CD4+T细胞的分化可塑性之间的关系，并分析其可能分子机制。本课题的预期结果能帮助我们更进一步了解T1DM的发病机制，提供早期预测T1DM的生物指标。

Pancreatic islet beta cells are directly destructed by cytotoxic CD8+ T cells, which need to be activated or regulated by CD4+ T cells. Upon activation, CD4+ T cells undergo differentiation according to the environmental signals and different functional subsets trigger different signalling pathway and interact with distinct immune cells. Our research group found that GATA3 was one of the risk genes and it is the key transcription factor in type 2 innate lymphoid cells (ILC2). Therefore, we hypothesized that GATA3 expression in ILC2 modulates the plasticity of CD4+ T cells and it might trigger the autoimmune response against islet beta cells. We would take advantage of BDC2.5 transgenic mice to set up an ILC2-islet beta cell antigen-specific CD4+ T cell experimental platform and challenge the recipient mice with different pathogens, including parasites and viruses. Moreover, we would like to challenge human peripheral blood mononuclear cells with the pathogens and see whether the genotypes of GATA3 affect its expression in ILC2 and thus alter the differentiate polarity of CD4+ T cells. The results will help us understand more about the development of T1DM and provide future biomarkers for early prediction of T1DM.