RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.
Asunto(s)
Homeostasis/inmunología , Inflamación/inmunología , Interleucina-10/inmunología , Intestinos/inmunología , Células Th17/inmunología , Animales , Plasticidad de la Célula/inmunología , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/inmunología , Staphylococcus aureus/fisiología , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-ß1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-ß signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-ß1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-ß signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-ß signaling. We show that TGF-ß, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.
