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 γt (RORγt)-gfp mice, we found that RORγt 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-1β, either in recombinant form or in supernatants from TLR4-activated dendritic cells. This innate-like ability of RORγt(+) nTh17 cells to respond to TLR4-induced cytokines was not shared by iTh17 cells. The other distinct properties of RORγt(+) nTh17 cells are their high expression of PLZF and their absence from lamina propria; iTh17 cells are found therein. RORγt(+) nTh17 cells are present in the thymus of germ-free RORγt-gfp and IL-6(-/-) RORΓ: t-gfp mice, indicating that these cells do not require symbiotic microbiota or IL-6 for their generation. Finally, we found that PLZF(+)RORγt(+) 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 RORγt 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.