Ετικέτες

Πέμπτη 20 Σεπτεμβρίου 2018

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 (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.



https://ift.tt/2pnaInk

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Αναζήτηση αυτού του ιστολογίου