p38α signaling programs dendritic cells to drive T(H)17 cell 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 that p38α MAP kinase programs DCs to drive T(H)17 differentiation. Deletion of p38α in DCs, but not macrophages or T cells, protects mice from T(H)17-mediated autoimmune neuroinflammation. p38α orchestrates expression of cytokines and co-stimulatory molecules in DCs, and further imprints T cell IL-23R signaling to promote T(H)17 differentiation. Moreover, p38α is required for tissue-infiltrating DCs to sustain T(H)17 responses. This activity of p38α is conserved between mouse and human DCs, and is dynamically regulated by pattern recognition and fungal infection. Our results identify p38α as a central pathway to integrate instructive signals in DCs for T(H)17 differentiation and inflammation.