CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

Hebbar Subramanyam, S.; Hriczko, J.; Look, T.; Goodarzi, T.; Clarner, T.; Verjans, E.; Boell, S.; Neullens, C.; Costa, I.; Gan, L.; Denecke, B.; Schippers, A.; Floess, S.; Huehn, J.; Schmitt, E.; Bopp, T.; Wasmuth, H.; Winograd, R.; Beyaert, R.; Lambrecht, B.; Boor, P.; Zenke, M.; Wagner, N.; Ohl, K.; Tenbrock, K.

doi:10.1101/2024.06.29.601312

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bioRxiv · 10.1101/2024.06.29.601312

CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

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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 ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/601312v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a2d341org.highwire.dtl.DTLVardef@1db6852org.highwire.dtl.DTLVardef@19e024borg.highwire.dtl.DTLVardef@a8c84d_HPS_FORMAT_FIGEXP M_FIG C_FIG Created by Biorender

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Hebbar Subramanyam, S., Hriczko, J., Look, T., Goodarzi, T., Clarner, T., Verjans, E., Boell, S., Neullens, C., Costa, I., Gan, L., Denecke, B., Schippers, A., Floess, S., Huehn, J., Schmitt, E., Bopp, T., Wasmuth, H., Winograd, R., Beyaert, R., Lambrecht, B., Boor, P., Zenke, M., Wagner, N., Ohl, K., Tenbrock, K.. 2024-07-02. CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses. https://doi.org/10.1101/2024.06.29.601312

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