Regulation of TH17 cell differentiation by innate immune signals

Upon antigen stimulation, naive T helper cells differentiate into distinct lineages to attain specialized properties and effector functions. T(H)17 cells, a recently identified lineage of CD4(+) effector T cells, play a key role in the immune defense against fungi and extracellular bacteria, but also contribute to the pathogenesis of many autoimmune conditions. The differentiation of T(H)17 cells is orchestrated by an intricate network of signaling pathways and transcriptional regulators in T cells. While the involvement of T cell-intrinsic pathways has been described extensively, we are just beginning to appreciate how T(H)17 cell development is shaped by extrinsic pathways, especially the innate immune signals. Dendritic cells (DCs), the most important cell type to bridge innate and adaptive immunity, drive T(H)17 cell differentiation by providing antigenic, costimulatory and cytokine signals. This is mediated by the recognition of innate and inflammatory signals by DCs via pattern recognition receptors, cytokine receptors and other immunomodulatory receptors that in turn activate the intracellular signaling network. In particular, p38α MAP kinase has emerged as a critical pathway to program DC-dependent T(H)17 cell differentiation by integrating multiple instructive signals in DCs. Here, we summarize the current knowledge on the mechanisms by which DC-derived innate immune signals drive T(H)17 cell differentiation.