Interleukin 9 (IL-9)-producing helper T (Th9) cells have a crucial function in allergic inflammation, autoimmunity, immunity to extracellular pathogens and anti-tumor immune responses. In addition to Th9, Th2, Th17 and Foxp3+ regulatory T (Treg) cells produce IL-9. A transcription factor that is critical for IL-9 induction in Th2, Th9 and Th17 cells has not been identified. Here we show that the forkhead family transcription factor Foxo1 is required for IL-9 induction in Th9 and Th17 cells. We further show that inhibition of AKT enhances IL-9 induction in Th9 cells while it reciprocally regulates IL-9 and IL-17 in Th17 cells via Foxo1. Mechanistically, Foxo1 binds and transactivates IL-9 and IRF4 promoters in Th9, Th17 and iTreg cells. Furthermore, loss of Foxo1 attenuates IL-9 in mouse and human Th9 and Th17 cells, and ameliorates allergic inflammation in asthma. Our findings thus identify that Foxo1 is essential for IL-9 induction in Th9 and Th17 cells.
γδ (gamma–delta) T cells, a small population of unconventional T cells, have been found in central nervous system lesions of multiple sclerosis (MS) patients, but their function in disease activity is not clearly understood. Previous studies in experimental autoimmune encephalomyelitis (EAE) were inconsistent in identifying their specific roles in suppressing or promoting disease pathogenesis. Emerging advancements in the biology of γδ T cells especially in the context of their being the major initial producers of IL-17, suggested their crucial role in pathogenesis of EAE. In addition, γδ T cells express high levels of IL-23R and IL-1R, which further enhance their effector functions in the pathogenesis of EAE. Nonetheless, activated heterogeneous γδ T cells display functional dichotomy, which is crucial in determining the outcomes of tissue inflammation in EAE. In this review, we discussed recent advances in understanding the biology of γδ T cells in tissue inflammation as well as their roles in suppressing or promoting the development of EAE.
BackgroundRecent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD).MethodsWe conducted a prospective study of U.S. women enrolled in the Nurses’ Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case–control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFβ1 or TH17 conditions.ResultsAmong a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells.ConclusionDietary potassium is inversely associated with risk of CD with both in vitro and gene–environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.
Interleukin (IL) 9-producing helper T (Th) 9 cells play a major role in contributing immunity against extracellular pathogens. In addition, the role of Th9 cells was demonstrated in the pathogenesis of allergic, skin, and intestinal inflammation. The functions of Th9 cells were further extended in antitumor immune response, as Th9 cells were suggested to be potent antitumor Th cells. Given the pleotropic functions of IL-9 in various pathophysiological conditions, it is essential to understand the differentiation and stability of Th9 cells and other IL-9-producing T cells. In addition to Th9 cells, Th2 and Th17 cells as well as induced Foxp3+ regulatory T cells (iTregs) cells also produce IL-9, but how IL-9 production is regulated in these cell types is not yet clearly defined. Although Th2, Th9 and Th17 cells as well as iTregs develop in the presence of distinct differentiating factors, yet they all express IL-9 together with their own lineage specific cytokines. Here, in this review, we summarize the current understanding of signaling pathways that lead to the promotion of differentiation of Th9 cells and IL-9 induction in Th2 and Th17 cells, as well as in iTregs. We further discuss the transcriptional regulation of Th9 cells in context of Foxo1, as an essential transcription factor required for the development and functions of Th9 and other IL-9-producing T cells.
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