Denecke, B. | Search bioRxiv

bioRxiv2024

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

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

immunology↗

bioRxiv2024

Underlying molecular effects to behavioral consequences present line of evidence for zebrafish eye development and function alteration by crude oil exposure.

Crude oil can affect the normal eye development and swimming behavior of fish embryos. In this study 0-4 hours post fertilization (hpf) zebrafish (Danio rerio) embryos were exposed to low, sublethal concentrations of water-accommodated fractions (WAF) of a naphthenic North Sea crude oil alone and in combination with a third-generation chemical dispersant. Effects on eye development and function at the transcript, histological, morphological, and behavioral level were assessed relative to untreated control specimen at 119 hpf. Exposed embryos swam significantly less during the dark phases of the light/dark transition test. Eye size of zebrafish embryos was significantly smaller in groups exposed to crude oil WAFs. Zebrafish retina histology revealed that, among other structural alterations, the outer nuclear layer, containing photoreceptor cells relevant for normal visual functioning, was significantly thinner in exposed embryos. Transcriptome analysis revealed that several genes involved in eye development and function (opsins and crystallins) were dysregulated upon oil exposure. The molecular effects on gene expression and eye histology results form a novel line of evidence that explains the observed effects of crude oil on the swimming activity of exposed fish embryos. The present study is in line with recent findings highlighting the importance of ocular toxicity in developing embryos exposed to petroleum samples at environmentally relevant and non-lethal concentrations without visible malformations. The study suggests that oculotoxicity should be considered as a major toxicity pathway alongside to the well-established cardiotoxicity.

developmental biology↗