Aire-Overexpressing Dendritic Cells Induce Peripheral CD4⁺ T Cell Tolerance.
Aire-Overexpressing Dendritic Cells Induce Peripheral CD4⁺ T Cell Tolerance.
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Aire 过表达树突状细胞诱导外周 CD4( ) T 细胞耐受
DOI：
10.3390/ijms17010038
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发表时间：
2015-12-29
影响因子：
5.6
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Li D;Li H;Fu H;Niu K;Guo Y;Guo C;Sun J;Li Y;Yang W
自身免疫调节因子(Aire)可以促进胸腺髓质上皮细胞(MTECs)外周组织限制性抗原(Tras)的异位表达，导致自身反应性T细胞的缺失，从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，仍然不清楚。本研究旨在探讨Aire过表达树突状细胞(Aire cell，Aire cell)对CD4+T细胞功能的影响及1型糖尿病(T1D)的治疗。我们证明了Aire细胞上调了STZ-T1D小鼠来源的脾细胞中耐受相关分子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细胞减少了STZ-T1D和WT小鼠来源的脾细胞中CD_4+干扰素-γ+T细胞的数量，并降低了CD_4+T细胞中TCR信号分子(钙和p-ERK)的表达水平。我们观察到Aire细胞诱导的CD4+T细胞可以延缓T1D的发育。综上所述，表达Aire的DC抑制了TcR信号通路，减少了CD4+干扰素-γ+自身反应性T细胞的数量。这些数据提示了Aire维持外周免疫耐受的机制，并提供了一种通过靶向Aire来控制自身免疫的潜在方法。
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 (Ca2+ 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.