Life Sciences | Medicine and Health Sciences
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.
Mitogen-activated protein kinases, including the ERK, JNK, and p38 MAPKs, are key intracellular signaling molecules used by eukaryotic cells to transduce a wide spectrum of extracellular signals (1–3). MAPKs play important roles in immune responses and regulate immune cell development, activation, differentiation, and survival. MAPK is activated through a cascade that also includes a MAPK kinase (MAP2K) and a MAP2K kinase (MAP3K). Upon stimulation of immune receptors or proinflammatory cytokine receptors, the MAPK pathways are rapidly induced, leading to the expression of genes that are essential for both the innate and adaptive immune responses (4–7). However, precisely how MAPKs are specifically induced and the physiological roles of individual MAPK cascades in T cell immunity remain to be fully elucidated.
MEKK3 is a member of the MAP3K superfamily and shares substantial homology in the kinase domain with other members in this family (8–10). Biochemical studies showed that MEKK3 is able to activate multiple MAPKs including the JNKs, ERK1/2, p38, and ERK5 MAPKs in vitro under certain conditions (11, 12). Mouse gene knockout studies showed that MEKK3 is essential for embryonic cardiovascular development, a function that cannot be compensated by its closest homologue MEKK2 (10, 13). Activation of MEKK3, like MEKK2, requires a dimerization-induced autophosphorylation on a conserved serine residue in its activation loop (14, 15). MEKK3 is involved in the proinflammatory cytokine- and TLR-induced JNK and p38 MAPK activation and is also required for IKK–NF-κB activation (16–19). Several studies, including two recent reports, suggest that MEKK3 may cooperate with another MAP3K, TAK1, and act downstream of E3 ubiquitin ligase TRAF6 in mediating the proinflammatory signals for MAPK and IKK–NF-κB activation (19–22). MEKK3 is constitutively expressed in both innate and adaptive immune cells, but little is known about the role of MEKK3 in adaptive immune responses.
Using a Mekk3 T cell conditional knockout (T-cKO) mouse line generated recently in our laboratory, we reported that MEKK3 is dispensable for thymic T cell development on the C57BL/6 background. However, the peripheral T cell homeostasis is impaired in the Mekk3 T-cKO mice (23). Similar phenotype in peripheral T cells homeostasis was also reported by another group with independently generated Mekk3 T-cKO mice (24).
To understand further the physiological role of MEKK3 in T cell-mediated adaptive immunity, we studied the function of Mekk3-deficient T cells and examined how MEKK3 deficiency affects the Ag-induced cytokine production, anti-bacteria immunity, and signal transduction pathways. Our results demonstrate that MEKK3 is required for mounting optimal T cell responses in vivo and is involved in mediating the TCR-dependent Rac1/2 signals for IFN-γ production through the MAPK pathways.
Wang, Xiaofang, "MEKK3 Regulates IFN-γ Production in T Cells through the Rac1/2-Dependent MAPK Cascades" (2011). UCHC Articles - Research. 208.