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Immunodeficient mice overexpressing IL‐9 develop more severe colitis mediated by IL‐9 activity on transferred CD4⁺ CD45RBhigh T cells. (A and B) Control medium or 2 × 10⁵ CD4⁺ CD45RBhigh lymphocytes isolated from FVB/c or IL‐9 Tg/c mice were injected into SCID mice. (A) Mice were weighted weekly and graph presents percentage of original weight. Mean values and SEM were calculated from five mice per group and are representative of five independent experiments. (B) Quantitative RT‐PCRs for Ifng, Il6, Tnfa, Il22, S100a8, Lcn2, Saa3, and Reg3g, performed on total RNA from colons of transferred SCID mice. Results were normalized to actin. Mean values and SEM were calculated from four to six mice of each group and are representative of two independent experiments. (C) Comparisons of the distal colonic mucosa of control SCID (left panel) and SCID mice treated 35 days before with 2 × 10⁵ CD4⁺ CD45RBhigh T cells, from either FVB/c (central panel) or IL‐9 Tg/c (right panel) mice. Bars represent the thickness of mucosa wall and the arrow points out ulceration of the epithelium. Representative sections of distal colon stained with H&E (at least four mice per group, representative of two experiments, scale bar, 100 µm and 20× magnification). (D and E) IL‐9 transgenic Rag2−/− mice were injected with control medium or CD4⁺ CD45RBhigh lymphocytes isolated from BALB/c or Il9r−/−/c animals. Mice received 4 × 10⁵ cells and were sacrificed 37 days after cell transfer. (D) Mice were weighed weekly and graph presents percentage of original weight. Mean values and SEM were calculated from five mice per group and are representative of three independent experiments. (E) Quantitative RT‐PCRs were performed for Ifng, Il6, Tnfa, Il22, S100a8, Lcn2, Saa3, and Reg3g, performed on total RNA from colons of transferred Rag2−/− mice. Results were normalized to actin. Mean values and SD were calculated from five mice of each group and are representative of three independent experiments. Statistical analyses: (A) two‐way ANOVA with Bonferroni post‐test; (B) Mann–Whitney test; (D) two‐way ANOVA with Bonferroni post‐test; (E) Mann–Whitney test (*p < 0.05, **p < 0.01; ***p < 0.005).
Source publication
IL‐9 is involved in various T cell‐dependent inflammatory models including colitis, encepahlitis and asthma. However, the regulation and specificity of IL‐9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4+C...
Citations
... Although T cell subsets that produce IL-9 have been described [21][22][23][24][25] , the effects of IL-9R signalling on T cells are not well characterized [26][27][28][29][30][31] . For example, naive T cells are insensitive to IL-9 and T cell development is unimpaired in IL-9-deficient mice, which suggests that IL-9 is not a critical natural cytokine in T cell biology 18,29,32 . We found that activated mouse T cells did not support IL-9 signalling (Fig. 1c) owing to the absence of IL-9R expression (Extended Data Fig. 1c,d), which underscores the unorthodoxy of o9R signalling in these cells 27,33,34 . ...
Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.
... Additionally, it has been also shown that IL-9 mediates Th17 differentiation in vitro [33,34]. Furthermore, pulmonary overexpression of IL-9 appears to induce Th2 differentiation leading to pathologic changes in the lungs [35]. Our findings for Th2 cells are also in accordance with these studies, and have further demonstrated that IL-9 deficiency significantly decreased Th2 cells infiltration and production of IL-4, IL-5, IL-13 and IL-17A; suggest that IL-9 can act on Th2 cells and Th17 cells, which are major contributors to allergic inflammation, either directly or indirectly. ...
Allergic asthma is an allergic inflammatory disease of the airways, in which numerous cell types and cytokines have been shown to contribute to pathogenesis of the disease. Although increased expression of IL-9 has been shown to influence the activity of structural as well as eosinophils and mast cells in asthma, the influence of IL-9 on function of ILC2 and Th2 cells remains unclear. This study therefore aimed to elucidate the role of IL-9 on ILC2 and Th2 cells using a murine model of asthma. A murine model of asthma was established using wild type (WT) and IL-9-deficient ( Il9 −/− ) transgenic mice sensitized to house dust mite (HDM). Bronchoalveolar lavage fluid (BALF) and lung tissues were collected, and analysed for inflammatory cells (eosinophils, mast cells, Th2 cells and ILC2 cells), histopathological changes, and several cytokines. HDM challenge significantly increased accumulation of ILC2 cells, Th2 cells and mast cells, as well as goblet cell hyperplasia, and the expression of cytokines IL-4, IL-5 and IL-13, but not IFN-γ, in WT mice compared to saline-challenged control group. In contrast, all pathological changes, including infiltration of ILC2 cells, Th2 cells and mast cells, were significantly attenuated in HDM-challenged Il9 −/− mice. Furthermore, the number of Ki67 ⁺ ILC2 cells, Ki67 ⁺ Th2 cells and Ki67 ⁺ mast cells were significantly reduced in the absence of IL-9 signalling. These data suggest that IL-9 promotes the proliferation and type 2 cytokine production of type 2 cells in the murine models of asthma, and therefore might be a potential therapeutic target for asthma treatment.
... Additionally, it has been also shown that IL-9 mediates Th17 differentiation in vitro 33,34 . Furthermore, pulmonary overexpression of IL-9 appears to induce Th2 differentiation leading to pathologic changes in the lungs 35 . ...
Asthma is an allergic inflammatory disease of the airways, in which numerous cell types and cytokines have been shown to contribute to pathogenesis of the disease. Although increased expression of IL-9 has been shown to influence the activity of structural as well as eosinophils and mast cells in asthma, the influence of IL-9 on function of ILC2 and Th2 cells remains unclear. This study therefore aimed to elucidate the role of IL-9 on ILC2 and Th2 cells using a murine model of asthma. A murine model of asthma was established using wild type (WT) and IL-9-deficient ( Il9 −/− ) transgenic mice sensitized to house dust mite (HDM). Bronchoalveolar lavage fluid (BALF) and lung tissues were collected, and analysed for inflammatory cells (eosinophils, mast cells, Th2 cells and ILC2 cells), histopathological changes, and several cytokines. HDM challenge significantly increased accumulation of ILC2 cells, Th2 cells and mast cells, as well as goblet cell hyperplasia, and the expression of cytokines IL-4, IL-5 and IL-13, but not IFN-γ, in WT mice compared to saline-challenged control group. In contrast, all pathological changes, including infiltration of ILC2 cells, Th2 cells and mast cells, were significantly attenuated in HDM-challenged Il9 −/− mice. Furthermore, the number of Ki67 ⁺ ILC2 cells, Ki67 ⁺ Th2 cells and Ki67 ⁺ mast cells were significantly reduced in the absence of IL-9 signalling. These data suggest that IL-9 promotes the proliferation and type 2 cytokine production of type 2 cells in the murine models of asthma, and therefore might be a potential therapeutic target for asthma treatment.
... In a DSS colitis model, anti-IL-9 blocking antibodies suppressed mucosal inflammation, and attenuation of disease was observed [142]. Adoptive transfer of IL-9-producing T cells into Rag2 knockout (Rag2 −/− KO) mice also induced colitis [143]. Furthermore, IL-9 was found to directly modulate the expression of tight junction proteins, claudin and occludin in the animal model of colitis [144]. ...
Interleukin-9 (IL-9) is a pleiotropic cytokine produced by several immune and epithelial cells. Recently, many studies have eluded the physiological and pathological roles of IL-9 and its lineage-specific helper T cell subset (Th9). In this chapter, we will focus on the immunological role of Interleukin 9 (IL-9) in allergy and autoimmunity. We will introduce the basics of IL-9 and describe the cells involved in the secretion, signaling, and regulation of IL-9. After establishing the background, we will discuss the pathogenesis and regulation of IL-9 in allergic and autoimmune diseases. We will conclude the chapter by providing an updated therapeutics that target IL-9 and their potential uses in autoimmune and allergic diseases.
... It is a consensus that UC is a disorder with multiple causative factors, in which aberrant immune response plays a critical role [4][5][6]. The immune system in the colon tissues of UC patients aberrantly overrespond to the commensal bacteria or innocent food proteins [4]. ...
Ulcerative colitis (UC) is a disease that frequently relapses and affects more than 0.1% general population; the underlying mechanism is poorly understood. Published data show that polymorphonuclear neutrophils (PMN) contribute to the pathogenesis of UC. This study aims to identify antigen (Ag)‐specific PMNs and investigate their role in UC relapse. In this study, the correlation between PMN activities and UC relapse was assessed in a group of UC patients. A UC mouse model was developed to expand the findings of UC patient study. The results showed that a positive correlation was detected between the high PMN activities and the food Ag‐specific IgG (sIgG) amounts in colon biopsies of UC patients. UC patient‐derived Ag‐specific PMNs could be activated upon exposure to food specific Ag (sAg). The Ag/FcγRI complexes were detected on the surface of PMNs in UC patients. Re‐exposure of sensitized PMNs to sAg triggered PMN activation and induced UC‐like inflammation in the mouse colon. We conclude that FcγRI play a critical role in UC relapse. Inhibition of FcγRI can efficiently inhibits experimental UC. This article is protected by copyright. All rights reserved
Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn's disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and the cytokine IL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.
Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease (IBD). It is a chronic, nonspecific, and inflammatory disease of the colon that is prone to repeated attacks and requires long-term maintenance treatment. Its clinical features include: diarrhea, weight loss, abdominal pain, fever, blood in the stool and the risk of cancer. It is currently believed that the pathogenesis of UC is due to environmental factors acting on genetically susceptible individuals, causing abnormal activation of the immune system and destruction of the intestinal mucosal barrier, resulting in inflammatory changes of the colonic mucosa, in which T cells and cytokines secreted by them is the important topics in UC pathogenesis research. Th9 cells are a newly discovered subset of T cells. IL-9 secreted by it has been shown to be involved in a variety of autoimmune disease. Now we will review the differentiation of Th9 cells and the mechanisms involved in the pathogenesis of UC.
Piglets are susceptible to weaning stress, which weakens the barrier and immune function of the intestinal mucosa, causes inflammation, and ultimately affects animal growth and development. Ellagic acid (EA) is a natural polyphenol dilactone with various biological functions. However, The mechanisms underlying the effects of EA on animal health are still poorly known. Herein, we examined whether dietary supplementation with EA has a positive effect on growth performance, intestinal health, immune response, microbiota, or inflammation in weaned piglets. Sixty weaned piglets (age, 30 days) were randomly divided into two groups: the control group (basic diet) and the test group (basic diet + 500 g/t EA). The pigs were fed for 40 days under the same feeding and management conditions, and the growth performance of each individual was measured. At the end of the feeding period, samples were collected from the small intestinal mucosa for further analysis. Using these tissues, the transcriptome sequences and intestinal microbial diversity were analyzed in both groups. An inflammation model using small intestinal mucosal epithelial cells (IPEC-J2) was also constructed. Dietary EA supplementation significantly increased the average daily weight gain (ADG) and reduced diarrhea rate and serum diamine oxidase (DAO) levels of weaned piglets. Transcriptome sequencing results revealed 401 differentially expressed genes in the jejunum mucosal tissue of pigs in the control and test groups. Of these, 163 genes were up-regulated and 238 were down-regulated. The down-regulated genes were significantly enriched in 10 pathways (false discovery rate < 0.05), including seven pathways related to immune response. The results of bacterial 16s rDNA sequencing show that EA affects the composition of the intestinal microbiota in the cecum and rectum, and reveal significant differences in the abundances of Prevotella_9, Lactobacillus delbrueckii, and Lactobacillus reuteri between the test and control groups (P < 0.05). Experiments using the inflammation model showed that certain doses of EA promote the proliferation of IPEC-J2 cells, increase the relative mRNA expression levels of tight junction-related proteins (ZO-1 and Occludin), improve the compactness of the intestine, reduce the expression of inflammatory factors TNF-α and IL-6, and significantly reduce LPS-induced inflammation in IPEC-J2 cells. In conclusion, we found for the first time that dietary supplementation of EA affects the gut immune response and promotes the beneficial gut microbiota in weaned piglets, reduces the occurrence of inflammatory responses, and thereby promotes the growth and intestinal health of piglets.
Objective
: Asthma is a chronic lung disease comprising multiple endotypes, and characterized by periodic exacerbations. A diverse array of T cells have been shown to contribute to all endotypes of asthma in pathogenic and regulatory roles. Here, we review the contributions of CD4+, CD8+, and unconventional T cells in allergic and non-allergic asthma.
Data Sources
: Review of published literature pertaining to conventional and unconventional T-cell types in asthma.
Study Selections
: Recent peer-reviewed articles pertaining to T cells in asthma, with additional peer-reviewed studies for context.
Results
: Much research in asthma has focused on the roles of CD4+ Th cells. Roles for Th2 cells in promoting allergic asthma pathogenesis have been well-described, and the recent description of pathogenic Th2a cells provides additional insight into these responses. Other Th types, notably Th1 and Th17, have been linked to neutrophilic and steroid-resistant asthma phenotypes. Beyond CD4+ T cells, CD8+ Tc2 cells are also strongly associated with allergic asthma. An emerging area for study is unconventional T-cell types, including gd T, iNKT, and MAIT cells. While data in asthma remains limited for these cells, their ability to bridge innate and adaptive responses likely makes them key players in asthma. A number of asthma therapies target T-cell responses, and, although data are limited, appear to modulate T-cell populations.
Conclusion
: Given the diversity and heterogeneity of asthma and T-cell responses, there remain many rich avenues for research to better understand the pathogenesis of asthma. Despite the breadth of T cells in asthma, approved therapeutics remain limited to Th2 networks.
