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. TH17 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 TH17 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 TH17 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 TH17 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 TH17 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 TH17 cell differentiation.