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

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 naive CD4(+) T cells with colitis, each over-express T-FH-associated gene products. Adoptive transfer of naive 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 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 T-FH-related gene expression, while If8(-/-)/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.