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The kinases MEKK2 and MEKK3 regulate transforming growth factor-?-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-? (TGF-?)-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-? 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-? responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-? signaling pathways is important in regulating Th cell differentiation.

SUBMITTER: Chang X 

PROVIDER: S-EPMC3073014 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Chang Xing X   Liu Fang F   Wang Xiaofang X   Lin Aiping A   Zhao Hongyu H   Su Bing B  

Immunity 20110217 2

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  ...[more]

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