Luciana Benevides1, Renata Sesti Costa1, Lucas Alves Tavares2, Momtchilo Russo3, Gislâine A Martins4, Luis Lamberti P da Silva2, L Karla Arruda5, Fernando Q Cunha6, Vanessa Carregaro1, João Santana Silva7. 1. Department of Biochemistry and Immunology, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil. 2. Department of Cellular and Molecular Biology, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil. 3. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. 4. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and Department of Medicine and Biomedical Science, Cedars-Sinai Medical Center (CSMC), Los Angeles, Calif. 5. Department of Clinical Medicine, Clinical Hospital of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. 6. Department of Pharmacology, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil. 7. Department of Biochemistry and Immunology, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil; Fiocruz-Bi-Institutional Translational Medicine Platform, Ribeirão Preto, Brazil. Electronic address: jsdsilva@fmrp.usp.br.
Abstract
BACKGROUND: The transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) has a key role in terminal differentiation in various T-cell subtypes. However, whether Blimp-1 regulates TH9 differentiation and its role in allergic inflammation are unknown. OBJECTIVE: We aimed to investigate the role of Blimp-1 in TH9 differentiation and in the pathogenesis of allergic airway inflammation. METHODS: In vitro TH9 differentiation, flow cytometry, ELISA, and real-time PCR were used to investigate the effects of Blimp-1 on TH9 polarization. T cell-specific Blimp-1-deficient mice, a model of allergic airway inflammation, and T-cell adoptive transfer to recombination-activating gene 1 (Rag-1)-/- mice were used to address the role of Blimp-1 in the pathogenesis of allergic inflammation. RESULTS: We found that Blimp-1 regulates TH9 differentiation because deleting Blimp-1 increased IL-9 production in CD4+ T cells in vitro. In addition, we showed that in T cell-specific Blimp-1-deficient mice, deletion of Blimp-1 in T cells worsened airway disease, and this worsening was inhibited by IL-9 neutralization. In asthmatic patients CD4+ T cells in response to TGF-β plus IL-4 increased IL-9 expression and downregulated Blimp-1 expression compared with expression in healthy control subjects. Blimp-1 overexpression in human TH9 cells inhibited IL-9 expression. CONCLUSION: Blimp-1 is a pivotal negative regulator of TH9 differentiation and controls allergic inflammation.
BACKGROUND: The transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) has a key role in terminal differentiation in various T-cell subtypes. However, whether Blimp-1 regulates TH9 differentiation and its role in allergic inflammation are unknown. OBJECTIVE: We aimed to investigate the role of Blimp-1 in TH9 differentiation and in the pathogenesis of allergic airway inflammation. METHODS: In vitro TH9 differentiation, flow cytometry, ELISA, and real-time PCR were used to investigate the effects of Blimp-1 on TH9 polarization. T cell-specific Blimp-1-deficient mice, a model of allergic airway inflammation, and T-cell adoptive transfer to recombination-activating gene 1 (Rag-1)-/- mice were used to address the role of Blimp-1 in the pathogenesis of allergic inflammation. RESULTS: We found that Blimp-1 regulates TH9 differentiation because deleting Blimp-1 increased IL-9 production in CD4+ T cells in vitro. In addition, we showed that in T cell-specific Blimp-1-deficient mice, deletion of Blimp-1 in T cells worsened airway disease, and this worsening was inhibited by IL-9 neutralization. In asthmatic patientsCD4+ T cells in response to TGF-β plus IL-4 increased IL-9 expression and downregulated Blimp-1 expression compared with expression in healthy control subjects. Blimp-1 overexpression in humanTH9 cells inhibited IL-9 expression. CONCLUSION:Blimp-1 is a pivotal negative regulator of TH9 differentiation and controls allergic inflammation.
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