Gadd45alpha regulates p38-dependent dendritic cell cytokine production and Th1 differentiation
Jirmanova, L.; Jankovic, D.; Fornace, A.J.; Ashwell, J.D.
Journal of Immunology 178(7): 4153-4158
2007
ISSN/ISBN: 0022-1767 PMID: 17371971 Document Number: 606426
Gadd45 alpha inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr(323). Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45 alpha(-/-) mice. Despite constitutively increased p38 activity in Gadd45 alpha(-/-) 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 alpha(-/-) 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 alpha(-/-) recipients had a diminished Th1 response to STAg, whereas Gadd45 alpha(-/-) T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45a has tissue-specific and opposing functions on p38 activity, and Gadd45 alpha-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.