LIGHT-LTβR/HVEM通路在1型糖尿病Tfh细胞分化中的作用机制

1型糖尿病（Type 1 Diabetes，T1D）是一种自身免疫性疾病，目前临床没有有效的治愈方法。NOD小鼠是研究T1D最常见的动物模型，在前期研究中我们成功构建LIGHT-/-NOD小鼠的基础上，我们首次发现LIGHT基因缺失显著衰减NOD小鼠T1D的发生。进一步的研究表明，与WT NOD小鼠相比，LIGHT-/-NOD小鼠CD4+ Treg细胞的百分率显著上调，但B细胞频率及功能却明显下调。Tfh细胞是导致T1D病理发生的关键细胞类型，且其形成与CD4+ Treg细胞和B细胞密切相关。据此推测：LIGHT通路可能通过调节自身反应性T细胞向Tfh细胞的分化来介导T1D的发生。本课题拟通过体内外实验，明确LIGHT通路在T1D Tfh细胞形成中的作用；探讨其促Tfh细胞分化的作用机制。预期结果不但有助于T1D的免疫调控机制的阐明，并且可为T1D免疫干预策略的发展提供重要的实验依据。

Type 1 diabetes is an autoimmune disease, and there isn't an effective treatment strategy for patients with T1D. Identifying the molecular mechanisms involved in the regulation in the type of immune response that underlies autoimmune tissue destruction is a critical step in designing appropriate immunomodulatory strategies. The spontaneous autoimmune diabetic NOD mice are used widely as the animal models in the study about T1D. In the previous studies, we established LIGHT -/- NOD mice successfully. It was found that, compared with the wild type NOD mice, the percentage of diabetes-free mice and CD4 +Treg cells was significantly increased, but B cells numbers and function were obviously down-regulated in the LIGHT -/- NOD mice. According to the literatures, CD4+ Treg cells control antigen-specific expansion of Tfh cell number via the coreceptor CTLA-4, and B cells are essential for Tfh cells differentiation. Moreover, Tfh cells play a critical role during the pathogenesis of Type 1 diabetes. We therefore hypothesized that LIGHT pathway mediates T1D development via the potentiating of Tfh cells differentiation. In the present studies, we will define the role of LIGHT pathway in the Tfh cells differentiation by collecting T1D patient samples and experiments in NOD mice, and then further explore the molecular and cellular mechanisms involved in LIGHT pathway regulation in Tfh cells formation by using the LIGHT-/- NOD mice and DO11RIP-mOVA mice -a transgenic mouse model of diabetes. Anticipative results will help us further unravel the precise pathogenesis of T1D, which may ultimately suggest novel treatment strategies for clinical disease.