树突状细胞（DC）通过摄取胰岛β细胞自身抗原，交叉呈递及激活T细胞免疫应答，破坏β细胞导致1型糖尿病（T1D）。最新发现自发性糖尿病小鼠（NOD）发病中大量产生一种功能独特的颗粒细胞型DC亚群（mcDC），其以非TIR通路依赖的方式破坏T细胞免疫耐受。承接前一项目研究发现mcDC可促进IFN-α分泌，减少α1-抗胰蛋白酶(AAT)释放，致使β细胞修复障碍。基于mcDC在T1D发病中的关键作用，我们拟首先通过细胞功能分析研究mcDC对调节性T细胞分化、结构稳定性和功能的影响，及对β细胞再生的干预；其次通过PCR array、蛋白分析确定阻断mcDC重建T细胞免疫耐受，促进β细胞再生的关键调控通路和信号分子；第三通过体内过继转移mcDC对T1D发病的影响确认关键靶标；最后通过抗T1D新型免疫抑制剂的分子机制研究，阐明靶向mcDC关键调控通路，评价T1D治疗药物的可行性，为T1D治疗提供新思路。

Dendritic cells (DC) present antigens from apoptotic β cells to stimulate effective T cell immune responses, which destroying β cells to induce type 1 diabetes. Recently, a new DC subset, termed merocytic dendritic cells (mcDC), has been found in NOD mice, and the frequency of which increases following onset of diabetes. These cells break antigen-specific T cell mediated immune tolerance via a toll-interleukin I receptor- independent signaling pathway. On the base of the previous study, we found that mcDC secreted higher level of IFN-α and less α1-antitrypsin(AAT) compared with normal DC, therefore preventing β cells repair. Regarding the key role of mcDC in the onset of T1D, we manage to conduct the following research: firstly analyze the effect of mcDC on differentiation, function and structural stability of Treg cells, as well as intervention on β cells regenesis by cell function assays; secondly identify the key regulation pathways and signal molecules that block mcDC to reconstruct T cells immune tolerance and improve β cell mass and function by PCR array and protein analysis; thirdly study the effect of adoptive transfer mcDC on onset of T1D via in vivo experiments to confirm the key drug targets; finally investigate the molecular mechanism of the novel immunosuppressive agent for controlling T1D, clarifying the possibility of target intervention on mcDC, which will provide evidences of novel strategy for treatment of T1D.