AIRE除表达于mTEC细胞维持中枢耐受外，还表达于外周DC细胞，但其在外周耐受中作用尚不明确。DC通过ICOSL介导TFH细胞分化，辅助自身反应B细胞活化，导致自身免疫病，TFR细胞可抑制TFH。研究报道AIRE缺陷鼠TFH增多，且我们发现AIRE缺陷鼠DC中ICOSL表达升高，因此推测DC中AIRE可能通过ICOSL影响TFH/TFR分化，维持外周耐受。本课题拟进行如下研究：1.利用动物模型观察AIRE与ICOSL表达及TFH/TFR细胞分化的关系；2.利用细胞模型确定AIRE是影响ICOSL表达的关键因素；3.利用基因表达调控技术探讨AIRE调控ICOSL表达的分子机制。4.利用T1DM模型综合分析AIRE通过调控ICOSL表达影响TFH/TFR细胞分化及在T1DM发病中的作用。为阐明AIRE在外周耐受中作用机制，并为以AIRE为靶点调控TFH/TFR分化治疗疾病提供实验依据。

AIRE expressing in mTEC maintain central tolerance. In addition, AIRE also express in peripheral dendritic cells. However it is not clear about its role in peripheral tolerance. ICOSL expressing on dendritic cells (DC) mediated the differentiation of TFH, which help the activation of autoreactive B cell and lead to autoimmune disease. TFR can suppress the function of TFH. It was reported that TFH increased in AIRE deficient mice. And we also found the increased expression of ICOSL on DC in AIRE deficient mice. So we suppose that AIRE expressing in DC may affect the differentiation of TFH/TFR via ICOSL, which mediate the peripheral tolerance. Here we will use the T1DM as disease model to study the following parts: 1. Using the animal model to observe the relationship between AIRE with ICOSL and TFH/TFR. 2. Using the cell model to determine if AIRE is the key factor to affect the ICOSL expression. 3. Using gene expression regulation techniques to investigate the molecular mechanisms of AIRE regulating ICOSL expression. 4. Using T1DM model for integrated analysis of the role of AIRE regulating the differentiation of TFH/TFR via ICOSL and its role in T1DM. This study will provide experimental evidence to clarify the mechanisms of AIRE in peripheral tolerance, and treat multiple diseases by modulating TFH/TFR via targeting AIRE.