T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation

Ruihua Zhang, Chen feng Qi, Yuan Hu, Yanhong Shan, Yuan Pang Hsieh, Feihong Xu, Geming Lu, Jun Dai, Monica Gupta, Miao Cui, Liang Peng, Jianjun Yang, Qingjie Xue, Ray Chen-Liang, Kang Chen, Yeyunfei Zhang, Wai Ping Fung-Leung, J. Rodrigo Mora, Liwu Li, Herbert C. MorseKeiko Ozato, Peter S. Heeger, Huabao Xiong

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The follicular helper T cell (T FH ) are established regulators of germinal center (GC) B cells, whether T FH have pathogenic potential independent of B cells is unknown. Based on in vitro T FH cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, T FH 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 T FH -associated gene products. Adoptive transfer of naïve Bcl6 −/− CD4 + T cells into Rag1 −/− recipient mice abrogated development of colitis and limited T FH differentiation in vivo, demonstrating a mechanistic link. In contrast, T cell deficiency of interferon regulatory factor 8 (IRF8) resulted in augmentation of T FH 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 T FH -related gene expression, while Irf8 −/− /Bcl6 −/− CD4 + T cells abrogated colitis, together indicating that IRF8-regulated T FH can directly cause colon inflammation. Molecular analyses revealed that IRF8 suppresses T FH differentiation by inhibiting transcription and transactivation of the TF IRF4, which is also known to be essential for T FH induction. Our documentation showed that IRF8-regulated T FH can function as B-cell-independent, pathogenic, mediators of colitis suggests that targeting T FH could be effective for treatment of IBD.

Original languageEnglish
Pages (from-to)113-122
Number of pages10
JournalJournal of Autoimmunity
Volume96
DOIs
StatePublished - Jan 2019

Keywords

  • Colitis
  • IRF4
  • IRF8
  • TFH

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