HLA基因是1型糖尿病（T1DM）最强易感基因，但其致病机制未明。本项目针对我国T1DM独特的临床表型，在T1DM易感HLA基因DRB1-DQA1-DQB1单倍型不全、分辨率不足等既往研究基础上，并结合T1DM易感HLA单倍型外显率逐年下降的趋势，拟首先明确中国T1DM人群经典HLA-I/II类基因单倍型。然后，在携带高危HLA单倍型纯合子T1DM个体中，筛选MHC分子限制性识别的特异性抗原肽；进而，以Notch信号通路为代表具有自我正反馈调控作用的共刺激分子为研究重点，探讨其促进“MHC分子-特异性抗原肽-T细胞受体”三分子复合物活化初始CD4+T淋巴细胞的分子机制；最后，利用Cre-LoxP重组酶系统，建立条件性树突状细胞、CD4+T细胞共刺激分子敲除转基因小鼠模型，在整体水平上探讨以具有上述特征的共刺激分子作为干预靶点，对延缓/逆转自身免疫性胰岛炎发生发展的作用。

HLA complex are the most susceptible genes for type 1 diabetes mellitus (T1DM). Yet the underlying mechanisms remain elusive. To understand if the unique clinical phenotypes of Chinese T1DM patients we observed previously were related to specific HLA haplotypes, typical HLA genes will be sequenced in a large T1DM population followed by MHC restricted antigen peptides screening in dendritic cells from high risk HLA haplotype carrying patients.The peptide-MHC-TCR complex will then be examined ex vivo to explore costimulatory molecules characterized by autoamplification regulation, such as Notch signaling pathway as we reported. Next, Conditional, tissue specific candidate costimulatory molecule deficient mice, such as notch, will be constructed and in vitro tri-molecular complex system will be adopted to explore the effects of this candidate costimulatory molecule. Finally CD4+ T cell depleted mice will be used to confirm if the deficiency of costimulatory molecule can attenuate naïve CD8+T cells activation-dependent autoimmune insulitis. The costimulatory molecule, as we propose, may serve as a new target for T1DM primary intervention in the future.