Dan Littman and colleagues report in Cell that the differentiation of interleukin-17 (IL-17)-producing pro-inflammatory T helper (TH) cells (known as TH17 cells) is directed by the transcription factor and nuclear hormone receptor retinoic-acid-related orphan receptor-γt (RORγt).

TH17 cells are the most recently discovered subset of TH cells, and they effect their role at the interface between the adaptive and the innate immune response. They regulate granulopoiesis and host defence against extracellular pathogens, and contribute markedly to the development of autoimmune disease. But what are the mechanisms that regulate the differentiation of this effector-cell subset? Littman and colleagues looked to the orphan nuclear receptor RORγt to answer this question. RORγt is required for development of the lymph nodes, the Peyer's patches and other lymphoid tissues, and the expression of RORγt by CD4+CD8+ (double positive) T cells has been shown to extend their survival during clonal selection.

DNA-microarray analysis of CD4+ T cells revealed that culture with IL-23 (which favours differentiation into TH17 cells) resulted in an increase in the amount of mRNA encoding RORγt. Because the authors had already found RORγt+ T cells in the intestinal lamina propria of mice, they were prompted to ask whether these cells were of the TH17-cell subset. A large proportion of lamina propria T cells were indeed found to produce IL-17, and RORγt was required for this expression. RORγt was also shown to be sufficient to induce the expression of IL-17 (and the related cytokine IL-17F) by naive CD4+ T cells that were stimulated with antigen, and it was required to induce IL-17 expression by these cells in response to IL-6 and transforming growth factor-β (TGFβ), cytokines that are known to induce IL-17 expression. Therefore, Littman and colleagues have shown that RORγt functions as a transcription factor downstream of IL-6 and TGFβ and is required for the differentiation of TH17 cells, both in vitro and in the lamina propria.

TH17 cells have been shown to be pathogenic in several animal models of autoimmune disease, including experimental allergic encephalomyelitis (EAE). So the authors induced EAE in both wild-type mice and RORγt-deficient mice, and they examined the role of RORγt in the development of EAE. Mice that lacked endogenous RORγt were less susceptible to EAE, and the presence of RORγt was shown to be required for the in vivo differentiation of pathogenic TH17 cells in the central nervous system during the EAE disease process.

Together, these results indicate that the transcription factor RORγt is a key immune regulator that directs the differentiation of TH17 cells, which are pro-inflammatory. Manipulating the activity of RORγt might therefore be an attractive strategy for the treatment of various inflammatory diseases.