title: Constitutive activation of MEK1 promotes Treg cell instability in vivo.
abstract: The instability of regulatory T (Treg) cells is involved in the pathogenesis of autoimmune diseases and also highlights safety concerns with regard to clinical Treg cell therapy. Cell-intrinsic molecular events linked to this Treg cell instability in vivo cells, which leads to safety concerns regardingare still obscure. Here we developed a novel luciferase-based reporter system and performed an unbiased screening for kinases that potentially modulate Foxp3 function. We found that the active form of COT/Tpl2 specifically inhibits the DNA binding activity of Foxp3 through a MEK-ERK-dependent pathway. Moreover, Treg cell-specific expression of activated MEK1 led to dysregulation of Treg function and instability of Foxp3 expression in vivo. Our results support the hypothesis that outside inflammatory signals act through the COT/Tpl2-MEK-ERK signaling pathway to destabilize the Treg lineage.
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China.
authors.forename: Jitao
authors.initials: J
authors.lastname: Guo
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China.
authors.forename: Xuejie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China.
authors.forename: Xundong
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CASPMI), Beijing 100101, China zhouxy@im.ac.cn.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D048369:MAP Kinase Kinase 1
keywords: Autoimmunity; Cell Signaling; Immunology; Inflammation; T Cell; Treg Cell, Instability, Foxp3, COT, MEK, ERK