MEKK3 Regulates IFN-gamma Production in T Cells through the Rac1/2-Dependent MAPK Cascades

作者：Wang Xiaofang; Zhang Fan; Chen Fanping; Liu Dou; Zheng Yi; Zhang Yongliang; Dong Chen; Su Bing^*

来源：The Journal of Immunology, 2011, 186(10): 5791-5800.

DOI：10.4049/jimmunol.1002127

MEKK3 is a conserved Ser/Thr protein kinase belonging to the MAPK kinase kinase (MAP3K) family. MEKK3 is constitutively expressed in T cells, but its function in T cell immunity has not been fully elucidated. Using Mekk3 T cell conditional knockout (T-cKO) mice, we show that MEKK3 is required for T cell immunity in vivo. Mekk3 T-cKO mice had reduced T cell response to bacterial infection and were defective in clearing bacterial infections. The Ag-induced cytokine production, especially IFN-gamma production, was impaired in Mekk3-deficient CD4 T cells. The TCR-induced ERK1/2, JNK, and p38 MAPKs activation was also defective in Mekk3-deficient CD4 T cells. In vitro, MEKK3 is not required for Th1 and Th2 cell differentiation. Notably, under a nonpolarizing condition (Th0), Mekk3 deficiency led to a significant reduction of IFN-gamma production in CD4 T cells. Furthermore, the IL-12/IL-18-driven IFN-gamma production and MAPK activation in Mekk3-deficient T cells was not affected suggesting that MEKK3 may selectively mediate the TCR-induced MAPK signals for IFN-gamma production. Finally, we found that MEKK3 activation by TCR stimulation requires Rac1/2. Taken together, our study reveals a specific role of MEKK3 in mediating the TCR signals for IFN-gamma production. The Journal of Immunology, 2011, 186: 5791-5800.

• 出版日期2011-5-15
• 单位中南大学