title: The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation.
abstract: Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3) negatively regulated transforming growth factor-β (TGF-β)-mediated Th cell differentiation. Map3k2(-/-)Map3k3(Lck-Cre/-) mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2(-/-)Map3k3(Lck-Cre/-) naive CD4(+) T cells' differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-β stimulation in vitro. In addition, Map3k2(-/-)Map3k3(Lck-Cre/-) mice developed more severe experimental autoimmune encephalomyelitis. Map3k2(-/-)Map3k3(Lck-Cre/-) T cells exhibited impaired phosphorylation of SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-β responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-β signaling pathways is important in regulating Th cell differentiation.
authors.affiliation: Department of Immunobiology and Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Chang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000032:analysis; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048730:MAP Kinase Kinase Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048748:MAP Kinase Kinase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D051899:Smad2 Protein / Q000737:chemistry / Q000378:metabolism*; D051900:Smad3 Protein / Q000737:chemistry / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000473:pathology; D058504:Th17 Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3; C482619:Map3k2 protein, mouse; C482626:Map3k3 protein, mouse