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

Publication date: Available online 19 September 2018

Source: Journal of Autoimmunity

Author(s): 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. Morse

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.

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