Signaling via the kinase p38α programs dendritic cells to drive TH17 differentiation and autoimmune inflammation

Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices remains unclear. We report here that the mitogen-activated protein kinase p38 alpha programmed DCs to drive the differentiation of the T(H)17 subset of helper T cells. Deletion of p38 alpha in DCs protected mice from T(H)17 cell-mediated autoimmune neuroinflammation, but deletion of p38 alpha in macrophages or T cells did not. We also found that p38 alpha orchestrated the expression of cytokines and costimulatory molecules in DCs and further 'imprinted' signaling via the receptor for interleukin 23 (IL-23R) in responding T cells to promote T(H)17 differentiation. Moreover, p38 alpha was required for tissue-infiltrating DCs to sustain T(H)17 responses. This activity of p38 alpha was conserved in mouse and human DCs and was dynamically regulated by pattern recognition and fungal infection. Our results identify p38 alpha signaling as a central pathway for the integration of instructive signals in DCs for T(H)17 differentiation and inflammation.