FOXO3公司
FOXP3型
福克斯O1
自身免疫
癌症研究
免疫学
生物
自身免疫性疾病
磷酸化
蛋白激酶B
免疫系统
免疫耐受
细胞生物学
抗体
作者
Xingrong Du,Hao Shi,Jiang Li,Yang Dong,Jie‐Liang Liang,Jian Ye,Shanshan Kong,Shujing Zhang,Tao P. Zhong,Zengqiang Yuan,Tian Xu,Yuan Zhuang,Biao Zheng,Jian-Guo Geng,Wufan Tao
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2014-02-15
卷期号:192 (4): 1525-1535
被引量:116
标识
DOI:10.4049/jimmunol.1301060
摘要
Abstract Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1−/− mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1−/− bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.
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