ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells
✍ Scribed by Josef Bodor; Zoltan Fehervari; Betty Diamond; Shimon Sakaguchi
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 493 KB
- Volume
- 37
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Abstract
Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25^+^CD4^+^ regulatory T cell (T~R~) assays mainly in activated Foxp3^–^ effector T cells and this induction correlates with sharp decrease in number of IL‐2‐expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25^–^CD4^+^ T cells antagonizes T~R~‐mediated suppression. Moreover, forced expression of Foxp3 in naive CD25^–^ T cells induces constitutive expression of ICER/CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/CREM both in Foxp3 transductants as well as CD25^–^ responder T cells suggesting that induction of T~R~ function in suppression assays may utilize contact‐dependent interaction. Indeed, CTLA‐4 blockade or use of B7‐deficient CD25^–^ responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL‐2 expression. Therefore, we propose that CTLA‐4 binding to B7 ligands expressed on activated ligand‐bearing Foxp3^–^ effector T cells results in ICER/CREM‐mediated transcriptional attenuation of IL‐2. Collectively, these data suggest that Foxp3 expression in T~R~ cells imposes suppression in contact‐dependent fashion by induction of constitutive ICER/CREM expression in activated CD25^+^ Foxp3^–^ T cell effectors thus preventing them from producing IL‐2.