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IL-9-producing T cells (T9) regulate immunological responses that affect various cellular biological processes, though their precise function remains fully understood. Previous studies have linked T9 cells to conditions such as allergic disorders, parasitic infection clearance, and various types of cancers. While the functional heterogeneity of IL-9 and T9 cells in cancer development has been documented, these cells present promising therapeutic opportunities for treating solid tumors. This review highlights the roles of IL-9 and T9 cells in cancer progression and treatment responses, focusing on potential discrepancies in IL-9/IL-9R signaling between murine tumors and cancer patients. Additionally, we discuss the regulation of tumor-specific Th9/Tc9 cell differentiation, the therapeutic potential of these cells, and current strategies to enhance their anti-tumor activities. • The roles of IL-9 and T9 cells in cancer progression are discussed. • T9 cells are promising in cancer immunotherapy. • Strategies to enhance T9 cells' anti-tumor effects in immunotherapy are explored. [ABSTRACT FROM AUTHOR]

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells. [ABSTRACT FROM AUTHOR]

Background: Food allergy (FA) is a common disease in children; thus, a high level of safety is required for its prevention and treatment. Colonic regulatory T cells (Tregs) have been suggested to attenuate FA. We investigated the Treg‐inducing ability and anti‐FA effects of carotenoids, a pigment contained in vegetables and fruits. Methods: C57BL/6N mice were fed a diet containing 0.01% (w/w) of lycopene, β‐carotene, astaxanthin or lutein for 4 weeks, and the population of colonic Tregs was assessed. Subsequently, to evaluate the Treg‐inducing ability of lycopene, splenic naïve CD4+ T cells from BALB/c mice were cultured with anti‐CD3/CD28 antibody, TGF‐β and lycopene, and the frequencies of Tregs were examined. The effect of 0.1% (w/w) lycopene containing diet on FA was investigated in OVA‐induced FA model BALB/c mice. Results: In screening, only lycopene significantly increased the frequency and number of colonic Tregs. Lycopene also increased Treg differentiation in splenic naïve CD4+ T cells. In FA mice, lycopene feeding significantly increased the number of colonic Tregs and attenuated allergic symptoms. The expression levels of IL‐4, IL‐9 and IL‐13 mRNA in colonic mucosa were also significantly reduced by lycopene. IL‐9 is known to induce proliferation of mast cells, and we found that lycopene feeding significantly reduced the number of mast cells in the colonic mucosa of FA mice. Conclusion: Our results suggest that lycopene, a carotenoid present in many common foods on the market, may have the potential to induce colonic Tregs and suppress FA symptoms. [ABSTRACT FROM AUTHOR]

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8+ or NK cells, there are clear evidences that CD4+ T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4+ T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa. These data might be important designing better interventions that unleash the full potential of immune response against cancer. [ABSTRACT FROM AUTHOR]

Tumor specific Th9 cells are potential effector cells for adoptive therapy of human cancers. TNF family members OX40L, TL1A and GITRL have been shown to promote the induction of Th9 cells and antitumor immunity. However, the role of TNF-α, the prototype of the TNF superfamily cytokines, in Th9 cell differentiation and their antitumor efficacy is not defined. Here, we showed that TNF-α potently promoted naïve CD4+ T cells to differentiate into Th9 cells in vitro. Furthermore, the addition of TNF-α during Th9 cell differentiation increased T cell survival and proliferation. More importantly, the adoptive transfer of TNF-α-treated Th9 cells induced more potent antitumor effects than regular Th9 cells in mouse tumor model. TNF-α signals via two cell surface receptors, TNFR1 and TNFR2. Mechanistic studies revealed that TNF-α drove Th9 cell differentiation through TNFR2 but not TNFR1. In addition, under Th9 polarizing condition, TNF-α activated STAT5 and NF-κB pathways in T cells in a TNFR2-dependent manner. Inhibition of STAT5 and NF-κB pathways by their specific inhibitors impaired TNF-α-induced Th9 cell differentiation. Our results identified TNF-α as a new powerful inducer of Th9 cells and clarified the molecular mechanisms underlying TNF-α-induced Th9 cell differentiation. [ABSTRACT FROM AUTHOR]

• Th9 cells (CD4+IL-9+) were highly expressed in Behçet's disease (BD) patients. • BD patients with pulmonary involvement expressed more Th9, IL-9 and PU.1 mRNA. • Significant correlations were observed between IL-9, IL-17 and TSLP n serum and in BAL. • Levels of IL-9, IL-17 and TSLP decreased in inactive BD patients after corticosteroïd treatment. • Macrophages secrete most of IL-9 than PBMCs. This increased was justified by the increased expression of the transcription factors PU.1 and IRF4. Behçet disease (BD) is a multisystemic disease some of whose manifestations are characterized by pulmonary involvements. The purpose of the study was to evaluate the level of T-helper type 9 (Th9) cells and the cytokine interleukin (IL)-9 in peripheral blood and in bronchoalveolar lavage (BAL) of patients with Behçet's disease (BD) affected by pulmonary manifestations. Nevertheless, until recently there have been no studies on its role in BD. The Th9 (CD4+IL-9+T) cell, transcription factor PU.1 and IL-9 mRNA levels, as well as serum and BAL IL-9 concentration, were measured in BD patients and healthy controls. The Th9 cell percentage and absolute number, PU.1 and IL-9 expression levels of BD patients were all increased significantly compared with the control group. Absolute number of Th9 cells was particularly increased in patients with active BD compared to inactive BD patients. The levels of IL-9 associated to Th9 expression depended on BD severity. These parameters were markedly expressed in the BAL of BD patients with pulmonary manifestations. IL-17 and the epithelial inflammatory cytokine TSLP were significantly correlated to IL-9 levels. This cytokine trio decreased in inactive BD patients after corticosteroïd treatment. In addition, IL-9 levels were correlated to CD4+ IL-9+ cells in BAL and in PBMCs. LPS stimulated PBMCs and macrophages induced increased secretion of IL-9 and the encoding transcription factors PU.1 and IRF4. In conclusion, the expansion of the Th9 cell subset, up-regulation of the PU.1 transcription factor and increased secretion of the IL-9 cytokine may contribute to the pathogenesis of BD, which may be supported by the increased release of IL-17 and TSLP. We provide evidence that Th9 T cells are increased in BD patients with pulmonary manifestations. This suggests an important role of IL-9 in the pathogenesis of BD particularly in patients suffering from lung involvement. [ABSTRACT FROM AUTHOR]

Background: Allergic contact dermatitis has been described as a type IV reaction caused by antigen‐specific T cells. Central roles for CD8+ cytotoxic T cells as effector cells and CD4+ T cells as regulatory cells have been suggested. T helper (Th) 2 and Th1 cytokines have been implicated; however, the nature of the allergen influences the Th response. Objective: To determine the types of T cells and cytokines expressed in patients allergic to p‐phenylenediamine (PPD). Methods: Serial skin biopsies of areas with positive patch test reactions in 29 PPD‐sensitized patients were collected. T cell markers and cytokine expression were analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction in both skin and peripheral blood mononuclear cells (PBMCs) of sensitized patients. Results: We observed increased expression of T cell markers and Th2/Th9‐associated cytokines in both skin and stimulated PBMCs of PPD‐allergic patients. Moreover, interleukin (IL)‐9 was mainly produced by Th9 cells, in both skin and PBMCs. Further investigations showed that Il9r‐deficient mice were more affected in a PPD contact hypersensitivity model than wild‐type mice. Conclusion: We did not confirm the preclinical presence of CD8+ T cells. However, the expression of different T cell markers positively correlated with patch test reactions. IL‐9 expression was strongly upregulated and directly related to patch test severity. In addition, we showed that IL‐9 has an anti‐inflammatory role in a mouse model of PPD contact hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine histologically characterized by indistinct sustained inflammatory responses. Genetical susceptibility and environmental factors’ effects play the roles in disease occurrence and it can be life threatening if remains untreated. It seems that intensification of inflammatory responses in this condition is not restricted to a specific cell line of T lymphocytes. Our aim was to determine the number of T helper 9 (Th9) cells in inflamed colonic biopsies of UC patients. We also correlated it with interleukin (IL)-9 protein level in addition to certain genes expressions associated with Th9 phenotype. Methods: Expression of CD4 and IL-9 were evaluated by immunohistochemical staining. Enzyme linked immunosorbent assay (ELISA) was performed to determine the colonic expression of IL-9 protein and finally mRNA expressions of interferon regulatory factor 4 (Irf4), Smad2, and Smad3 were measured by real-time polymerase chain reaction (RT-PCR) as critical transcription factors of Th9 differentiation. Results: Number of Th9 cells was significantly increased in inflamed samples as compared with normal tissues. Also quantitative measurement of IL-9 by ELISA and mRNA expressions of Irf4, Smad2, and Smad3 showed notable correlative enhancements in patient’s samples. Conclusion: Function and number of Th9 cells are up-regulated in the inflamed mucosa of UC patients as with the protein secretion of IL-9 and mRNA expressions of Irf4, Smad2, and Smad3, so Th9 cells and IL-9 may become remarkable therapeutic targets for IBD treatment in the future. [ABSTRACT FROM AUTHOR]

T lymphocytes represent an important part of adaptive immune system undertaking different functions to regulate immune responses. CD4+ T cells are the most important activator cells in inflammatory conditions. Depending on the type of induced cells and inflamed sites, expression and activity of different subtypes of helper T cells are changed. Recent studies have confirmed the existence of a new subset of helper T lymphocytes called Th9. Naive T cells can differentiate into Th9 subtypes if they are exposed simultaneously by interleukin (IL) 4 and transforming growth factor β and also secondary activation of a complicated network of transcription factors such as interferon regulatory factor 4 (IRF4) and Smads which are essential for adequate induction of this phenotype. Th9 cells specifically produce interleukin 9 and their probable roles in promoting intestinal inflammation are being investigated in human subjects and experimental models of ulcerative colitis (UC). Recently, infiltration of Th9 cells, overexpression of IL-9, and certain genes associated with Th9 differentiation have been demonstrated in inflammatory microenvironment of UC. Intestinal oversecretion of IL-9 protein is likely to break down epithelial barriers and compromise tolerance to certain commensal microorganisms which leads to inflammation. Th9 pathogenicity has not yet been adequately explored in UC and they are far from being considered as inflammatory cells in this milieu, therefore precise understanding the role of these newly identified cells in particular their potential role in gut pathogenesis may enable us to develop novel therapeutic approaches for inflammatory bowel disease. So, this article tries to discuss the latest knowledge on the above-mentioned field. [ABSTRACT FROM AUTHOR]

Background: This study was to investigate association and potentially destructive role of Th9/IL-9 and their synergistic interaction with Th17 cells in elevating MMP9 production in local lesions of oral lichen planus (OLP) patients.Methods: Oral mucosal tissues were obtained from OLP patients and healthy controls (HC) and then divided into an epithelial part (EP) or a lamina propria part (LP). Both EP and LP subsets were assessed for IL-9 and MMP9 mRNA levels by real-time quantitative PCR (qPCR). Flow cytometry was used to detect the CD4+ T helper subset Th9 (IL-9+ IL-17- CD4+ ) and Th17 (IL-9- IL-17+ CD4+ ) in co-cultured CD4+ Th cells and oral keratinocytes of OLP. IL-9, IL-17, and MMP9 in co-culture supernatant were detected by ELISA.Results: The qPCR results demonstrated that IL-9 and MMP9 mRNA levels were positively correlated in OLP lesions, and both significantly elevated in EP and LP lesions of erosive type OLP. Th9 and Th17 cells were significantly elevated in co-cultures of CD4+ Th cells and keratinocytes, and MMP9, IL-9, and IL-17 levels were simultaneously increased. In vitro, recombinant human IL-17 treatment significantly enhanced MMP9 protein and mRNA levels, while a synergistic effect of IL-9 and IL-17 was not observed. However, further results showed Th17 cells, IL-17, and MMP9 were increased significantly when recombinant IL-9 was added to the cultured CD4+ T cells.Conclusion: This study demonstrated that Th9/IL-9 can induce elevated levels of MMP9 to aggravate OLP disease severity, which may occur directly through increasing Th17 levels or indirectly through a synergistic role with Th17. [ABSTRACT FROM AUTHOR]

Infection in humans with Leishmania manifests into a spectrum of diseases. The manifestations of the disease depend on the resultant evasion of the parasite to immune responses namely macrophages, which is an exclusive host of leishmania. The B cells valiantly mount antibody responses, however to no avail as the Leishmania parasites occupy the intracellular niches of the macrophages. Extensive studies have been documented on the role of cell-mediated immunity (CMI) in protection and counter survival strategies of the parasites leading to down-regulation of CMI. The present review attempts to discuss the cytokines in progression or resolution of visceral form of leishmaniasis or kala-azar, predominantly affecting the Indian subcontinent. The components/cytokine(s) responsible for the regulation of the critical balance of Th1/Th2/Th9/Th17/Treg cells has been discussed in the perspective. Therefore, any strategy involving the treatment of VL needs to consider the balance and regulation of CD4+ T cell function. [ABSTRACT FROM AUTHOR]

Objective Oral lichen planus (OLP) presents with large numbers of T lymphocytes accumulating beneath the epithelium of the oral mucosa; however, its aetiology remains obscure. A potential role for an emerging novel T cell subset, Th9, in OLP has recently been suggested but remains to be clarified. The current aim was to investigate the expression and potential clinical significance of Th9 cells in distinct subtypes of OLP. Materials and methods Peripheral blood samples were collected from 41 OLP patients and 18 healthy controls (HCs). Flow cytometric analysis was used to detect the CD4+ T helper subset Th9 (IL-9 + IL-17 − CD4 + Th cells) and Th17 (IL-9 − IL-17 + CD4 + Th cells) expression levels. Results Flow cytometry results showed significantly elevated levels of Th9 cells in reticular and erosive OLP compared to HCs. Th9 expression in erosive OLP was less than in reticular OLP, indicating that Th9 but not Th17 cells may play a predominant role in reticular disease. However, in erosive OLP patients, we found much higher levels of Th17 cells compared to reticular OLP patients and HCs, indicating that Th17 dominates in erosive OLP. Statistical analysis showed positive correlations of Th9 cells and Th17 cells in patients with reticular or erosive OLP but none in HCs. Conclusions Th9 and Th17 cells may take the predominant roles in reticular and erosive OLP respectively, and their numbers were positively correlated in reticular and erosive OLP patients. Elevated circulating Th9 cells may help maintain immune balance in OLP immunopathogenesis, which requires further investigation. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor (TNF) receptors and their corresponding cytokine ligands have been implicated in many aspects of the biology of immune functions. TNF receptors have key roles during various stages of T cell homeostasis. Many of them can co-stimulate lymphocyte proliferation and cytokine production. Additionally, several TNF cytokines can regulate T cell differentiation, including promoting Th1, Th2, Th17, and more recently the newly described Th9 subset. Four TNF family cytokines have been identified as regulators for IL-9 production by T cells. OX40L, TL1A, and GITRL can promote Th9 formation but can also divert iTreg into Th9, while 4-1BBL seems to inhibit IL-9 production from iTreg and has not been studied for its ability to promote Th9 generation. Regulation of IL-9 production by TNF family cytokines has repercussions in vivo, including enhancement of anti-tumor immunity and immunopathology in allergic lung and ocular inflammation. Regulating T cell production of IL-9 through blockade or agonism of TNF family cytokine receptors may be a therapeutic strategy for autoimmune and allergic diseases and in tumor. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (DM1) is a chronic inflammatory disease, which when progresses leads to the development of late vascular complications. The disease involves impairments in regulatory and effector subsets of T lymphocytes, which suppress and maintain inflammatory response, respectively. ST2/IL-33 pathway is involved in T-cell-mediated immune response and might regulate the inflammatory process in several diseases. This review presents the latest research findings regarding effector and regulatory T cell subsets in the context of inflammation accompanying DM1 with particular focus on the ST2/IL-33 network and its possible association with T cell-mediated immunity. [ABSTRACT FROM AUTHOR]

Th9 cells are a new subset of helper T cells, and the signature cytokine for Th9 cells is IL-9. Both Th9 cells and Th9 products are implicated in multiple disease settings. Thus, a clear understanding of how Th9 cells are induced and controlled is an important and clinically relevant issue. There are different molecular pathways identified thus far in the induction of Th9 cells, and activation of such diverse pathways requires integration of signals from TGF-β and IL-4 cytokine receptors as well as costimulatory molecules. These signals converge on the induction of multiple transcription factors that collectively drive the development of Th9 cells. [ABSTRACT FROM PUBLISHER]

Since birth, our immune system is constantly bombarded with self-antigens and foreign pathogens. To stay healthy, complex immune strategies have evolved in our immune system to maintain self-tolerance and to defend against foreign pathogens. Effector T cells are the key players in steering the immune responses to execute immune functions. While effector T cells were initially identified to be immune promoting, recent studies unraveled negative regulatory functions of effector T cells in modulating adaptive as well as innate immunity. Owing to their critical and diverse functions in controlling immune responses, the functions and regulation of effector T cells have been a subject of intense investigation. In this review, key information about T cell immunity is summarized. [ABSTRACT FROM AUTHOR]

Abstract: The physiopathology of systemic sclerosis remains unclear within a complex interaction between vasculopathy, perivascular inflammatory infiltrate, extensive tissue fibrosis and auto-immune manifestations. Chronology between vascular disease and adjacent inflammatory cell infiltration is still not yet clarified. There is growing evidence that T cell activation and its cytokine expression play a key role in vascular impairment occurrence and collagen dysregulation. Nevertheless, cytokine descriptions are mainly limited to blood and tissue measurement and the T cells differentiation analysis restricted to the Th1/Th2 balance. The purpose of this review is to establish an exhaustive cartography of cytokines involved in T cell differentiation, regarding the recent advance in T lymphocyte differentiation, including Th9, Th17, Th22 and regulatory T cells (Treg) pathways. This review will focus on Th17, Th22 and Treg differentiation, corresponding to the equilibrium between inflammation and tolerance. Finally, regarding published results in systemic sclerosis, T cells participation appears to be more a Th1/Th2 co-expression than an exclusive Th1 or Th2 polarization. Also, a possible Th22/Treg imbalance is suggested, leading to a Th22 overexpression and likely to tissue inflammation genesis. [Copyright &y& Elsevier]

The cardinal features of asthma include pulmonary inflammation and airway hyperresponsiveness (AHR). Classically, asthma, specifically allergic asthma, has been attributed to a hyperactive Th2 cell immune response. However, the Th2 cell-mediated inflammation model has failed to adequately explain many of the clinical and molecular aspects of asthma. In addition, the outcomes of Th2-targeted therapeutic trials have been disappointing. Thus, asthma is now believed to be a complex and heterogeneous disorder, with several molecular mechanisms underlying the airway inflammation and AHR that is associated with asthma. The original classification of Th1 and Th2 pathways has recently been expanded to include additional effector Th cell subsets. These include Th17, Th9 and Treg cells. Emerging data highlight the involvement of these new Th cell subsets in the initiation and augmentation of airway inflammation and asthmatic responses. We now review the roles of these recently classified effector Th cell subsets in asthmatic inflammation and the insights they may provide in addition to the traditional Th2 paradigm. The hope is that a clearer understanding of the inflammatory pathways involved and the mediators of inflammation will yield better targeted therapeutics. [ABSTRACT FROM AUTHOR]

Resistance can occur in patients receiving adoptive cell therapy (ACT) due to antigen-loss-variant (ALV) cancer cell outgrowth. Here we demonstrate that murine and human T helper (Th) 9 cells, but not Th1/Tc1 or Th17 cells, expressing tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs), eradicate advanced tumors that contain ALVs. This unprecedented antitumor capacity of Th9 cells is attributed to both enhanced direct tumor cell killing and bystander antitumor effects promoted by intratumor release of interferon (IFN) α/β. Mechanistically, tumor-specific Th9 cells increase the intratumor accumulation of extracellular ATP (eATP; released from dying tumor cells), because of a unique feature of Th9 cells that lack the expression of ATP degrading ectoenzyme cluster of differentiation (CD) 39. Intratumor enrichment of eATP promotes the monocyte infiltration and stimulates their production of IFNα/β by inducing eATP-endogenous retrovirus-Toll-like receptor 3 (TLR3)/mitochondrial antiviral signaling (MAVS) pathway activation. These results identify tumor-specific Th9 cells as a unique T cell subset endowed with the unprecedented capacity to eliminate ALVs for curative responses. [Display omitted] • Th9 cells eradicate advanced tumors containing antigen-loss-variant cancer cells • Lack of CD39 on Th9 cells increase the intratumor accumulation of eATP • eATP-ERVs-TLR3/Mavs-type I IFN pathway is activated in the recruited monocytes • Type I IFN induced in the recruited monocytes cells causes the elimination of ALVs Tumor heterogeneity and antigen loss cause tumor relapse or progression after cancer adoptive cell immunotherapy. Xue et al. uncover that tumor-specific Th9 cells not only kill antigen-positive cancer cells but kill antigen-negative cancer cells in tumors, which holds promise to advance the utility and efficacy of adoptive cell immunotherapy. [ABSTRACT FROM AUTHOR]

• The Blimp-1 expression was negatively correlated with IL-9 in DM-CHD patients. • Blimp-1 has a protective effect on DM-CHD rats. • Blimp-1 inhibited Th9 cell differentiation in DM-CHD rats. • Blimp-1 alleviated endothelial dysfunction, oxidative stress in DM-CHD rats. • Blimp-1 expression was decreased in DM-CHD patients and rats. Diabetic coronary heart disease (DM-CHD) poses a major threat to the world. The newly described T cell subset-Th9 cells and related cytokine interleukin (IL)-9 play important roles in the pathogenesis of diabetes and atherosclerosis. B lymphocyte-induced maturation protein 1 (Blimp-1) has been indicated to negatively regulate Th9 development in allergic asthma, but its role in DM-CHD remains unclear. Hence, this study was designed to investigate the role of Blimp-1 in DM-CHD and to elucidate whether the mechanism was associated with regulation of Th9 cell differentiation. Our results showed that serum Blimp-1 mRNA level was decreased whereas proportion of Th9 cells (IL-9+ CD4+ T cells) and serum level of Th9-related IL-9 were increased in DM-CHD patients. Furthermore, serum Blimp-1 mRNA level was negatively correlated with IL-9 level in DM-CHD patients. Importantly, administration of lentiviruses expressing Blimp-1 (LV-Blimp-1) significantly inhibited Th9 cell differentiation and alleviated the severity of atherosclerotic lesions in the aorta and coronary artery, dyslipidemia, inflammation, vascular endothelial dysfunction, and oxidative stress in DM-CHD model rats. Collectively, Blimp-1 exerts a protective effect in DM-CHD rats and the mechanism might involve inhibition of Th9 cell differentiation. [ABSTRACT FROM AUTHOR]

Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9 , Irf4 , and Batf3 , even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance. • Endogenous polyamine synthesis is essential for the GATA3 expression during T helper 2 (Th2) cell differentiation. • Polyamine synthesis inhibition upregulated the expression of Th9-related genes such as IL-9 under Th2-skewing conditions. • Polyamine synthesis inhibition augmented IL-9 production under Th2 and Th9-skewing conditions. • Deprivation of polyamines increased IL-9-producing CD4+ T cells in vivo. [ABSTRACT FROM AUTHOR]