GADD45β/GADD45γ and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNγ production in T cells

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Abstract
The stress‐inducible molecules GADD45β and GADD45γ have been implicated in regulating IFNγ production in CD4 T cells. However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro . Here we generated MEKK4‐deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4−/− mice have reduced p38 activity and defective IFNγ synthesis. Expression of GADD45β or GADD45γ promotes IFNγ production in MEKK4+/+ T cells, but not in MEKK4−/− cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of GADD45β and GADD45γ on p38 activation and IFNγ production. During Th1 differentiation, the GADD45β/GADD45γ/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNγ production in a process independent of STAT4.