Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease.
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.
State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Diseases, School of Life Sciences, Fudan University, Shanghai 200433, China;
Xingrong
X
Du
Hao
H
Shi
Jiang
J
Li
Yongli
Y
Dong
JieLiang
J
Liang
Jian
J
Ye
Shanshan
S
Kong
Shujing
S
Zhang
Tao
T
Zhong
Zengqiang
Z
Yuan
Tian
T
Xu
Yuan
Y
Zhuang
Biao
B
Zheng
Jian-Guo
JG
Geng
Wufan
W
Tao
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D000099317:Hippo Kinases
D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000090742:Serine-Threonine Kinase 3; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse