Department of Immunobiology and Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06519, USA.
Immunity. 2011 Feb 25;34(2):201-12. doi: 10.1016/j.immuni.2011.01.017. Epub 2011 Feb 17.
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.
丝裂原活化蛋白激酶（MAPK）是 T 细胞受体（TCR）信号的关键介质，但它们在辅助性 T（Th）细胞分化中的作用尚不清楚。在这里，我们发现 MAPK 激酶激酶 MEKK2（由 Map3k2 编码）和 MEKK3（由 Map3k3 编码）负调控转化生长因子-β（TGF-β）介导的 Th 细胞分化。Map3k2(-/-)Map3k3(Lck-Cre/-) 小鼠在外周表现出调节性 T（Treg）和 Th17 细胞的异常积累，与 Map3k2(-/-)Map3k3(Lck-Cre/-) 幼稚 CD4(+) T 细胞分化为 Treg 和 Th17 细胞的情况一致，这些细胞在体外经 TGF-β刺激后的分化频率高于野生型（WT）细胞。此外，Map3k2(-/-)Map3k3(Lck-Cre/-) 小鼠发生更严重的实验性自身免疫性脑脊髓炎。Map3k2(-/-)Map3k3(Lck-Cre/-) T 细胞表现出 SMAD2 和 SMAD3 蛋白在其连接区的磷酸化受损，这负调控了 T 细胞中的 TGF-β反应。因此，TCR 诱导的 MAPK 和 TGF-β 信号通路之间的串扰对于调节 Th 细胞分化很重要。
