Background The transcription factor cAMP response element modulator (CREM) is a widely expressed transcriptional repressor. CREMα is overexpressed in SLE (Systemic Lupus erythematosus) T cells and CREMα promoter activity correlates with disease activity. Occurrence of autoreactive B and T cells is a hallmark of this severe autoimmune disease. Autoreactive immune responses are normally controlled by regulatory T cells (Tregs). This T cell population is regulated by FoxP3 as the most important and lineage-specific transcription factor. Several studies observed that numbers and suppressive capacity of regulatory T cells are decreased in SLE patients and in murine lupus models. Until now the reason for these observations remains to be elucidated. We showed before that overexpression of CREMα accelerates onset of auto-immune mediated disease in a murine model of lupus. Interestingly these mice also show decreased levels of regulatory T cells.
Objectives The aim of this study was to elucidate the role of CREMα in regulatory T cells.
Methods We assessed the role of CREMα in regulatory T cells by analyzing numbers and suppressive capacity of this cell population in CREMα overexpressing and CREM deficient mice. We performed reporter gene assays to investigate transcriptional regulation of FoxP3 expression.
Results We observed enhanced numbers of regulatory T cells in CREM deficient mice, as well as enhanced levels of FoxP3 mRNA expression and an increased differentiation towards FoxP3 positive cells in vitro. Vice versa FoxP3 mRNA expression and differentiation towards FoxP3 positive cells was reduced in mice which overexpress CREMα. Furthermore CREM deficient regulatory T cells showed an enhanced suppressive capacity in vitro and in vivo. We attribute these findings to an involvement of CREMα in transcriptional regulation of FoxP3 expression. We found that CREMα binds and trans-represses activity of the regulatory T cell-specific demethylated region in the FoxP3 locus, which is known to critically regulate FoxP3 expression.
Conclusions We postulate that increased expression of CREMα in SLE T cells mediates an exaggerated down-regulation of FoxP3 expression and compromises stability and function of Tregs. This data provide further evidence for CREMα as a key player in the development of autoimmunity.
Disclosure of Interest None Declared
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