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

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.