CREB REGULATES FOXP3+ST-2+TREGS WITH ENHANCED IL-10 PRODUCTION

ABSTRACT Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs. First it downregulates Foxp3 expression, however in cooperation with CREM, CREB expression in Tregs alters chromatin accessibility to the ST-2 region and thereby influences T cell specific immune responses mediated by IL-10. Brief summary: Mice with a Foxp3-specific knockout of CREB display enhanced expression of IL-13, IL-10, ST-2 and CREM, which prevents gut inflammation GRAPHICAL ABSTRACTCreated by Biorender Competing Interest Statement The authors have declared no competing interest. Footnotes ↵# Bernd Denecke unfortunately passed away during the project The authors have declared that no conflict of interest exists. The revised manuscript has been refined to focus specifically on the impact of CREB deletion in regulatory T cells (Tregs) in relation to colitis. This updated version includes new data from adoptive transfer colitis experiments using Foxp3creCREBfl/flROSARFP mice, providing a more comprehensive analysis of CREB's role in Treg function during intestinal inflammation. Supplemental figures have also been added to support the main findings and offer further insights into the mechanisms involved. Additionally, the author affiliations have been updated, reflecting any changes in institutional associations. Overall, the manuscript offers a targeted exploration of the molecular mechanisms underlying Treg-mediated suppression of colitis, potentially providing valuable insights into therapeutic strategies for inflammatory bowel diseases.