Early regulatory B cell induction and Th/Tr17 responses relates to success of long-term grass-pollen AIT
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118243 | GEO | 2018/10/29
REPOSITORIES: GEO
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Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice
2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress
Project description:Inflammation is a beneficial host response to infection, but it also contributes to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (i.e., they can cease to express their signature cytokine, IL-17A) and plasticity (i.e., they can start expressing cytokines typical of other lineages) upon in vitro re-stimulation. However technical limitations prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as “transdifferentiation”. Furthermore, while Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two novel fate-mapping mouse models to track Th17 cells during immune responses to show that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a global change in their transcriptome and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF- β signaling and the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases. We isolated intestinal lymphocytes from two independent experiments, each using 5 mice injected with anti-CD3 mAb. Th17, exTh17, Tr1 exTh17, Tr1, Foxp3 Treg and Foxp3 IL-10+ Treg cell populations were FACS-sorted from these two independent experiments and the cells of each population were pooled before the analysis. Around 5,000 cells for each population were processed.
2015-04-25 | E-GEOD-68242 | biostudies-arrayexpress
Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma.
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Project description:Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d-lipid presentation by Bregs induces iNKT cells to secret IFN-γ to contribute, partially, to the down-regulation of T helper (Th)1 and Th17 adaptive immune responses for ameliorating experimental arthritis. Mice lacking CD1d-expressing B cells develop exacerbated diseases compared to wild-type mice, and fail to respond to α-galactosylceramide treatment. Absence of lipid presentation by B cells causes altered activation of iNKT cells, with disruption of regulatory pathways including those involved in metabolism and cytokine responses. Thus, we identify an IL-10-independent mechanism by which Bregs restrain excessive inflammation via lipid presentation.
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2020-03-25 | PXD016633 | Pride
Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4. Crucial for T helper17 (Th17) cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification7-10. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. 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 naïve 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 and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Mouse T helper 17 cell differentiation with or without TGFB
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Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (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 argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. 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 naïve 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 and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.
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Project description:Inflammation is a beneficial host response to infection, but it also contributes to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (i.e., they can cease to express their signature cytokine, IL-17A) and plasticity (i.e., they can start expressing cytokines typical of other lineages) upon in vitro re-stimulation. However technical limitations prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as “transdifferentiation”. Furthermore, while Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two novel fate-mapping mouse models to track Th17 cells during immune responses to show that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a global change in their transcriptome and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF- β signaling and the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.
2015-04-25 | GSE68242 | GEO
Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
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