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The Journal of Immunology, 2006, 176: 4616-4621.
Copyright © 2006 by The American Association of Immunologists

Selective Requirement of p38{alpha} MAPK in Cytokine-Dependent, but Not Antigen Receptor-Dependent, Th1 Responses1

Lisa S. Berenson*, Jianfei Yang2,*,{dagger}, Barry P. Sleckman*, Theresa L. Murphy* and Kenneth M. Murphy3,*,{dagger}

* Department of Pathology and Center for Immunology, and {dagger} Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110

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 p38{alpha} in Th1 differentiation, we generated Ag-specific p38{alpha}+/– 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 Th1 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.




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