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Gadd45 Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation¹

Ludmila Jirmanova^*, Dragana Jankovi, Albert J. Fornace, Jr. and Jonathan D. Ashwell^2,*

^* Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892; and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057

Gadd45 inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr³²³. Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45^–/– mice. Despite constitutively increased p38 activity in Gadd45^–/– T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45^–/– DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45^–/– recipients had a diminished Th1 response to STAg, whereas Gadd45^–/– T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45 has tissue-specific and opposing functions on p38 activity, and Gadd45-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jonathan D. Ashwell, Laboratory of Immune Biology, Building 37, Room 3002, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. E-mail address: jda{at}pop.nci.nih.gov

³ Abbreviations used in this paper: DC, dendritic cells; SEA, Schistosoma mansoni egg Ags; STAg, Toxoplasma gondii Ags; MEKK, MEK kinase; WT, wild type; KO, knockout; MKK, MAP kinase kinase.