Abstract
The development of Th17 cells is accompanied by the acquisition of responsiveness to both IL-12 and IL-23, cytokines with established roles in the development and/or function of Th1 and Th17 cells, respectively. IL-12 signaling promotes antigen-dependent Th1 differentiation but, in combination with IL-18, allows the antigen-independent perpetuation of Th1 responses. On the other hand, while IL-23 is dispensable for initial commitment to the Th17 lineage, it promotes the pathogenic function of the Th17 cells. In this study, we have examined the overlap between Th1 and Th17 cells in their responsiveness to common pro-inflammatory cytokines and how this affects the antigen-independent cytokine responses of Th17 cells. We found that in addition to the IL-1 receptor, developing Th17 cells also up-regulate the IL-18 receptor. Consequently, in the presence of IL-1β or IL-18, and in the absence of TCR activation, Th17 cells produce Th17 lineage cytokines in a STAT3-dependent manner when stimulated with IL-23, and IFN© via a STAT4-dependent mechanism when stimulated with IL-12. Thus, building on previous findings of antigen-induced plasticity of Th17 cells, our results indicate that this potential of Th17 cells extends to their cytokine-dependent antigen-independent responses. Collectively, our data suggest a model whereby signaling via either IL-1β or IL-18 allows for bystander responses of Th17 cells to pathogens or pathogen products that differentially activate innate cell production of IL-12 or IL-23.
Highlights
Th17 cells are characterized by the production of IL-17A, IL-17F and IL-22 and perform diverse roles in tissue immunity
Naïve OT-II TCR transgenic mice (OT-II) TCR transgenic CD4 T cells were cultured for 5 days under Th1- or Th17-polarizing conditions, the latter in the presence or absence of IL-23
Consistent with published results [10, 24], Il12rβ1 and Il23r were up-regulated on Th17 cells and the expression of both increased in the presence of IL-23 (Fig 1D and 1E)
Summary
Th17 cells are characterized by the production of IL-17A, IL-17F and IL-22 and perform diverse roles in tissue immunity. Th17 cells are induced by the combined actions of TGFβ and IL-6 on TCR-activated naïve CD4 T cells which promote expression of the lineage-associated transcription factors, RORγt [1], RORα [2] and IRF4 [3]. IL-6, as well as IL-21 –an autocrine factor induced by IL-6, promote up-regulation of the IL-23 receptor (IL-23R) [4, 5] in parallel to IFNγ-induced up-regulation of the IL-12Rβ2 on Th1 cells [6,7,8]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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