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21333552
The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation.

Immunity, 2011/2/25;34(2):201-12.

Chang X[1], Liu F, Wang X, Lin A, Zhao H, Su B

Affiliations

PMID: 21333552DOI: 10.1016/j.immuni.2011.01.017

Impact factor: 43.474

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.
MeSH terms
Animals; Bone Marrow Transplantation; Cell Differentiation; Enzyme Activation; Forkhead Transcription Factors; Lymphocyte Count; Lymphopenia; MAP Kinase Kinase Kinase 2; MAP Kinase Kinase Kinase 3; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Processing, Post-Translational; Protein Structure, Tertiary; Receptors, Antigen, T-Cell; Smad2 Protein; Smad3 Protein; Specific Pathogen-Free Organisms; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta
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