Selective requirement of p38α MAPK in cytokine-dependent, but not antigen receptor-dependent, Th1 responses

The role of the p38 MAPK pathway in Th1 development has been controversial, because indirect manipulations of either upstream p38 activators or modifiers of p38 activity have had variable effects on IFN-gamma production in CD4(+) T cells. Uncertainties regarding the specificity of pharmacologic inhibition or p38 dominant negative mutants diminish the strength of conclusions about the role of the p38 alpha isoform in Th1 development. Also, the effects of some upstream p38 activators, such as MAPK kinase 3, on Th1 development are not as strong as the effects of other manipulations, such as the expression of a dominant negative p38 mutant. Finally, embryonic lethality has prevented a direct examination of p38 alpha-deficient T cells. To test the requirement for p38a in Th1 differentiation, we generated Ag-specific p38a(+/-) and p38 alpha(-/-) CD4(+) T cells using RAG2(-/-) blastocyst complementation and retroviral expression of the DO11.10 TCR. IFN-gamma production in response to TCR signaling is normal in p38 alpha(-/-) T cells cultured in Th1 conditions, implying normal Thl development. However, p38 alpha(-/-) Th1 cells have a much greater defect in IFN-gamma secretion stimulated by IL-12/IL-18 compared with TCR-induced IFN-gamma secretion. These results suggest that the activity of p38 alpha in Th1 cells is relatively restricted to acting in one of two alternative pathways (i.e., cytokine induced) that can induce the production of IFN-gamma in differentiated Th1 cells, but that p38 alpha is not required for the process of Th1 commitment and development itself.