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T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.
Zhang, Ruihua; Qi, Chen-Feng; Hu, Yuan; Shan, Yanhong; Hsieh, Yuan-Pang; Xu, Feihong; Lu, Geming; Dai, Jun; Gupta, Monica; Cui, Miao; Peng, Liang; Yang, Jianjun; Xue, Qingjie; Chen-Liang, Ray; Chen, Kang; Zhang, Yeyunfei; Fung-Leung, Wai-Ping; Mora, J Rodrigo; Li, Liwu; Morse, Herbert C; Ozato, Keiko; Heeger, Peter S; Xiong, Huabao.
Afiliação
  • Zhang R; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Qi CF; Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Hu Y; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Shan Y; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Hsieh YP; Department of Biological Sciences, College of Science, Virginia Tech, USA.
  • Xu F; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Lu G; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Dai J; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Gupta M; Programs in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • Cui M; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Peng L; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Yang J; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Xue Q; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Chen-Liang R; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Chen K; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.
  • Zhang Y; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Fung-Leung WP; Janssen Research & Development, LLC., CA 92121, USA.
  • Mora JR; Janssen R&D, Spring House, PA 19477, USA.
  • Li L; Department of Biological Sciences, College of Science, Virginia Tech, USA.
  • Morse HC; Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Ozato K; Programs in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • Heeger PS; Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: peter.heeger@mssm.edu.
  • Xiong H; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: huabao.xiong@mssm.edu.
J Autoimmun ; 96: 113-122, 2019 01.
Article em En | MEDLINE | ID: mdl-30241692
The follicular helper T cell (TFH) are established regulators of germinal center (GC) B cells, whether TFH have pathogenic potential independent of B cells is unknown. Based on in vitro TFH cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, TFH and its functions in colitis development were analyzed by FACS, ChIP, ChIP-sequencing, WB, ELISA and PCR. Herein we demonstrate that intestinal tissues of patients and colon tissues obtained from Rag1-/- recipients of naïve CD4+ T cells with colitis, each over-express TFH-associated gene products. Adoptive transfer of naïve Bcl6-/- CD4+ T cells into Rag1-/- recipient mice abrogated development of colitis and limited TFH differentiation in vivo, demonstrating a mechanistic link. In contrast, T cell deficiency of interferon regulatory factor 8 (IRF8) resulted in augmentation of TFH induction in vitro and in vivo. Functional studies showed that adoptive transfer of IRF8 deficient CD4+ T cells into Rag1-/- recipients exacerbated colitis development associated with increased gut TFH-related gene expression, while Irf8-/-/Bcl6-/- CD4+ T cells abrogated colitis, together indicating that IRF8-regulated TFH can directly cause colon inflammation. Molecular analyses revealed that IRF8 suppresses TFH differentiation by inhibiting transcription and transactivation of the TF IRF4, which is also known to be essential for TFH induction. Our documentation showed that IRF8-regulated TFH can function as B-cell-independent, pathogenic, mediators of colitis suggests that targeting TFH could be effective for treatment of IBD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos B / Doença de Crohn / Linfócitos T Auxiliares-Indutores / Colite / Colo / Centro Germinativo / Fatores Reguladores de Interferon Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Autoimmun Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos B / Doença de Crohn / Linfócitos T Auxiliares-Indutores / Colite / Colo / Centro Germinativo / Fatores Reguladores de Interferon Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Autoimmun Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos