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 (T_FH) 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 (<i>CD4</i>^<i>cre</i><i>Atf3</i>^<i>fl/fl</i> ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of T_FH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from <i>CD4</i>^<i>cre</i><i>Atf3</i>^<i>fl/fl</i> mice compared with <i>Atf3</i>^<i>fl/fl</i> littermate controls. The defective T_FH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of T_FH or IgA⁺ B cells caused significant remission of colitis in <i>CD4</i>^<i>cre</i><i>Atf3</i>^<i>fl/fl</i> mice, indicating the T_FH-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 T_FH cells in the gut, which may represent a potential immunotherapeutic target in colitis.