Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

By K. Ghoreschi, A. Laurence, Xiang-Ping Yang, C. Tato, M. McGeachy, J. Konkel, Haydeé L. Ramos, Lai Wei, Todd S. Davidson, N. Bouladoux and 11 more. Nature, 2010

1,234 citations recorded by the source corpus.

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity. Although crucial for TH17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/5afb51da483814973987f1a509ddb51c69fdb660

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

Citations in the corpus

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease (2011, background): “This alternate mode of T H 17 differentiation, dependent on IL23R expression, seems to have a greater pathogenic role than TGF-β–induced T H 17 differentiation, highlighting the value of discovering protective variants in autoimmunit”
RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation (2011, background): “In agreement with that observation, the importance of TGF-β in the generation of pathogenic T H 17 cells has also been dismissed and the role of IL-23 independently of IL-17 expression has been revaluate”
IL-6 in inflammation, autoimmunity and cancer (2020, background): “The produced IL-6 further induces T h 17 cell differentiation through STAT3 in the presence of TGF β , IL-1 β and IL-23, all of which are rich in inflammatory lesions and tumor microenvironments (164, 166, 169–171, 174, 175).”