title: MEKK3 regulates IFN-gamma production in T cells through the Rac1/2-dependent MAPK cascades.
abstract: 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-γ 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-γ production in CD4 T cells. Furthermore, the IL-12/IL-18-driven IFN-γ 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-γ 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-γ production.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.|Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520.|Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.|Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520.|Xiang-Ya Hospital, Central South University, Changsha 410008, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Xiang-Ya Hospital, Central South University, Changsha 410008, China.
authors.forename: Fanping
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.|Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Dou
authors.initials: D
authors.lastname: Liu
authors.affiliation: Children's Hospital Research Foundation, Cincinnati, OH 45229.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.|Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D056704:Adaptive Immunity; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005434:Flow Cytometry; D015151:Immunoblotting; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000634:Aminoquinolines; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D048748:MAP Kinase Kinase Kinase 3; D020928:Mitogen-Activated Protein Kinases; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C487513:NSC 23766; C482626:Map3k3 protein, mouse