Transcriptional factor ATF3 protects against colitis by regulating follicular helper T cells in Peyer’s patches

Abstract

Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4+T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4+T cells (CD4creAtf3fl/fl) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of TFHcells, not other T cell subsets, were dramatically decreased in Peyer’s patches fromCD4creAtf3fl/flmice compared withAtf3fl/fllittermate controls. The defective TFHcells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFHor IgA+B cells caused significant remission of colitis inCD4creAtf3fl/flmice, indicating the TFH–IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4+T cells. In summary, we demonstrated ATF3 as a regulator of TFHcells in the gut, which may represent a potential immunotherapeutic target in colitis.