Deficiency of Autophagy in Dendritic Cells Protects against Experimental Autoimmune Encephalomyelitis
Deficiency of Autophagy in Dendritic Cells Protects against Experimental Autoimmune Encephalomyelitis
复制标题
DOI：
10.1074/jbc.m114.575860
复制
发表时间：
2014-09-19
影响因子：
4.8
通讯作者：
Eissa, N. Tony
中科院分区：
文献类型：
--
作者：
Bhattacharya, Abhisek;Parillon, Xyanthine;Eissa, N. Tony
树突状细胞（Dendritic cells，DCs）是免疫系统中功能最强的抗原提呈细胞（antigen-presenting cells，APC）。DC在I类或II类MHC的背景下将抗原呈递给CD 8和CD 4 T细胞。最近的证据表明，自噬，一个保守的细胞内降解途径，调节II类抗原呈递。体外研究表明，自噬相关基因的缺失减少了APC向CD 4 T细胞的抗原呈递。体内研究证实了这些发现在感染性疾病的背景下。然而，自噬介导的抗原呈递在自身免疫中的相关性仍有待阐明。在这里，我们报告说，自噬相关基因7（Atg 7）在DC的损失改善实验性自身免疫性脑脊髓炎（EAE），CD 4 T细胞介导的多发性硬化症的小鼠模型，通过减少在体内的T细胞引发。相反，半抗原诱导的接触超敏反应的严重程度，其中CD 8 T细胞和NK细胞发挥主要作用，不受影响。在EAE发作前给予自噬-溶酶体抑制剂氯喹可延缓疾病进展，在发作后给予可降低疾病严重程度。我们的数据显示，自噬是诱导EAE所必需的，并表明自噬可能是治疗CD 4 T细胞介导的自身免疫性疾病的潜在靶点。
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in the immune system. DCs present antigens to CD8 and CD4 T cells in the context of class I or II MHC. Recent evidence suggests that autophagy, a conserved intracellular degradation pathway, regulates class II antigen presentation. In vitro studies have shown that deletion of autophagy-related genes reduced antigen presentation by APCs to CD4 T cells. In vivo studies confirmed these findings in the context of infectious diseases. However, the relevance of autophagy-mediated antigen presentation in autoimmunity remains to be elucidated. Here, we report that loss of autophagy-related gene 7 (Atg7) in DCs ameliorated experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-mediated mouse model of multiple sclerosis, by reducing in vivo priming of T cells. In contrast, severity of hapten-induced contact hypersensitivity, in which CD8 T cells and NK cells play major roles, was unaffected. Administration of the autophagy-lysosomal inhibitor chloroquine, before EAE onset, delayed disease progression and, when administered after the onset, reduced disease severity. Our data show that autophagy is required in DCs for induction of EAE and suggest that autophagy might be a potential target for treating CD4 T cell-mediated autoimmune conditions.