Li Dongbei, Li Haijun, Fu Haiying, Niu Kunwei, Guo Yantong, Guo Chuan, Sun Jitong, Li Yi, Yang Wei
Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.
Int J Mol Sci. 2015 Dec 29;17(1):38. doi: 10.3390/ijms17010038.
Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study's aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4⁺ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4⁺ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4⁺ IFN-γ⁺ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca(2+) and p-ERK) in CD4⁺ T cells. We observed that Aire cells-induced CD4⁺ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4⁺IFN-γ⁺ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire.
自身免疫调节因子（Aire）可促进外周组织限制性抗原（TRA）在胸腺髓质上皮细胞（mTEC）中的异位表达，从而导致自身反应性T细胞的清除，进而预防自身免疫性疾病。然而，Aire在外周的功能，如在树突状细胞（DC）中的功能，仍不清楚。本研究的目的是探讨过表达Aire的DC（Aire细胞）对CD4⁺T细胞功能及1型糖尿病（T1D）治疗的影响。我们证明，Aire细胞可上调STZ-T1D小鼠来源脾细胞中耐受性相关分子CD73、Lag3和FR4的mRNA水平以及CD4⁺T细胞的凋亡。此外，在胰岛素刺激后，Aire细胞可减少STZ-T1D和野生型小鼠来源脾细胞中CD4⁺IFN-γ⁺T细胞的数量，并降低CD4⁺T细胞中TCR信号分子（Ca(2+)和p-ERK）的表达水平。我们观察到，Aire细胞诱导的CD4⁺T细胞可延缓T1D的发展。总之，表达Aire的DC抑制TCR信号通路并减少CD4⁺IFN-γ⁺自身反应性T细胞的数量。这些数据提示了Aire在外周免疫耐受维持中的机制，并提供了一种通过靶向Aire来控制自身免疫的潜在方法。
