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

Abstract

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

Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis

“…Therefore, the balance between Tfr and Tfh10/Tfh17 cells is critical in the pathogenesis of autoimmune diseases (Wang et al, 2018). Higher numbers of Tfh17 or lower numbers of Tfh10 and Tfr cells can lead to inflammatory immunological damage in the colonic mucosa (Zhang et al, 2019). As shown in the present study, SSP can inhibit the decrease in Tfr and Tfh10 cells and the increase in Tfh17 cells to restore the balance of Tfr to Tfh10/Tfh17cells.…”

“…It has been shown that high expression of Tfh-cell-related genes leads to development of IBD (Zhang et al, 2019). Clinical trials have shown that the balance of Tfr and Tfh cells is closely related to IBD (Wang et al, 2019b).…”

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

“…Journal of Immunology Research that can bind to AP1-IRF4 complexes and regulate Tfh cell differentiation [50,51]. IRF8 plays various and important regulatory roles in the growth, differentiation, and function of immune cells in inflammatory bowel disease (IBD) patients [19]. IRF8 inhibits the differentiation of Tfh cells by directly binding to the promoter region of the IRF4 gene and inhibiting the transcription and activation of IRF4.…”

“…IRF8 inhibits the differentiation of Tfh cells by directly binding to the promoter region of the IRF4 gene and inhibiting the transcription and activation of IRF4. In contrast, IRF8 deficiency significantly enhances IRF4 binding the promoter region of the IL-21 gene and results in the expansion of Tfh cell differentiation in vitro and in vivo [ 19 ].…”

Gut Microbiota Modulation on Intestinal Mucosal Adaptive Immunity

“…Activating transcription factor 3 (ATF3) can protect against colitis by regulating Tfhs in the gut [69]. Interferon regulatory factor 8- (IRF8-) regulated Tfhs can function as pathogenic mediators of colitis in IBD, which is independent of B cells [70]. Transcription factor c-Maf is expressed early in Tfh cell precursors and identified as a regulator in the differentiation of Tfh cells in a cell-autonomous fashion [71].…”