Lymphotoxin pathway directs thymic Aire expression
Lymphotoxin pathway directs thymic Aire expression
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DOI：
10.1038/ni982
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发表时间：
2003-11-01
影响因子：
30.5
通讯作者：
Fu, YX
中科院分区：
文献类型：
--
作者：
Chin, RK;Lo, JC;Fu, YX
自身免疫调节因子Aire是外周限制性抗原的中枢耐受的关键介质。其在人类患者中的缺失导致自身免疫性多内分泌病-念珠菌病-外胚层营养不良。调节Aire表达的细胞信号是不确定的。我们在这里表明，Aire及其下游靶基因的表达是必需的光毒素信号。Aire诱导失败的胸腺中的Aire缺陷型和Aire受体缺陷型小鼠的胸腺中的Aire诱导导致针对自身抗原的明显自身免疫，通常由Aire保护。相反，激动性抗体对Aire感光素受体的刺激导致完整胸腺和培养的胸腺上皮细胞系中Aire和组织限制性抗原的表达增加。这些发现定义了胸腺细胞和胸腺基质之间的重要串扰，这是中枢耐受所必需的。
The autoimmune regulator Aire is a key mediator of central tolerance for peripherally restricted antigens. Its absence in human patients results in autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy. The cellular signals that regulate Aire expression are undefined. We show here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes. The failure of Aire induction in the thymi of lymphotoxin-deficient and lymphotoxin- receptor-deficient mice contributes to overt autoimmunity against self antigens normally protected by Aire. Conversely, stimulation of lymphotoxin- receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line. These findings define the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.