TLR-induced cytokines promote effective proinflammatory natural Th17 cell responses.

Naive CD4 lymphocytes undergo a polarization process in the periphery to become induced Th17 ( iTh17) cells. Using retinoic acid-related orphan receptor gamma t (ROR gamma t)-gfp mice, we found that ROR gamma t and the transcription factor promyelocytic leukemia zinc finger ( PLZF) are valuable new markers to identify the recently described natural Th17(nTh17) cell population. nTh17 cells are thymically committed to promptly produce large amounts of IL-17 and IL-22. In this study, we show that, in addition to responding to TCR cross-linking, nTh17 cells secrete IL-17 and IL-22 when stimulated with IL-23 plus IL-1 beta, either in recombinant form or in supernatants from TLR4-activated dendritic cells. This innate-like ability of ROR gamma t(+) nTh17 cells to respond to TLR4-induced cytokines was not shared by iTh17 cells. The other distinct properties of ROR gamma t(+) nTh17 cells are their high expression of PLZF and their absence from lamina propria; iTh17 cells are found therein. ROR gamma t(+) nTh17 cells are present in the thymus of germ-free ROR gamma t-gfp and IL-6(-/-) ROR gamma t-gfp mice, indicating that these cells do not require symbiotic microbiota or IL-6 for their generation. Finally, we found that PLZF(+)ROR gamma t(+) nTh17 cells represent one of the primary IL-17-producing innate-like T cell populations in a TLR7 imiquimod model of psoriasis-like disorder, indicating their involvement in this kind of lesion. Collectively, our results reveal ROR gamma t and PLZF as characteristic markers for identifying nTh17 cells and demonstrate one of their novel properties: the ability to respond promptly to TLR-dependent proinflammatory stimuli without TCR engagement, placing them as members of the innate-like T cell family.