cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

Abstract

Appropriate expression of IL-2 plays a central role during the priming and differentiation of T cells. A tight balance between IL-2 and the effector cytokine IL-17A is essential for immune homeostasis. Epigenetic mechanisms have been documented as a key component of cytokine regulation during lineage commitment. The molecular mechanisms that induce chromatin remodeling are less well understood. We investigated epigenetic regulators that mediate the diametric expression of IL-2 and IL-17A in naive, central memory, and effector memory CD4 + T cells. We demonstrate that cAMP response modulator (CREM)α contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREMα also reduces CpG-DNA methylation of the IL17A promoter. CREMα expression is regulated at the epigenetic level by CpG-DNA methylation, which allows increased CREMα expression in effector memory CD4 + T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREMα and exhibit a phenotype that is similar to effector memory CD4 + T cells with epigenetically predetermined expression patterns of IL-2 and IL-17A. We conclude that CREMα mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease.inflammation | gene regulation

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

“…We reported recently that CaMK4 can activate the transcription factor CREM-α (19,20), which mediates epigenetic remodeling of cytokine genes, including IL17 during the priming of CD4 + T cells from patients with SLE (35,53). Consistent with this, MRL/lpr.Camk4 -/-mice exhibited reduced CREM-α recruitment to the Il17 promoter, which led to decreased IL-17, arguing that the CaMK4-CREM-α…”

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

“…Conflicting data exist regarding Stat5 in SLE (21,22). Although attenuated IL-2 expression in SLE T cells suggests reduced Stat5 activation (23)(24)(25), one study demonstrated increased Stat5 phosphorylation in SLE (22). In T cells from SLE patients and lupus-prone MRL/lpr mice, pStat3 is increased (19,26).…”

“…Expression plasmids for human DNMT3a have been described previously (24). Reporter constructs spanning the proximal 946 bp of the human IL10 promoter or a 630 bp-spanning fragment of the fourth intron with enhancer activity were PCR-amplified and cloned into luciferase vector pGL3-Basic (Promega).…”

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

“…CREMα was found to bind to the IL17 promoter and to enhance its activity in vitro. In addition to the promoter, CREMα binds to additional sites across the IL17 locus but, unlike the IL2 locus, keeps the IL17 locus open because it fails to recruit HDAC1, G9α, and DNMT1 (67). Thus it appears that a single transcription factor, CREMα, accounts for both increased IL-17 production and decreased IL-2 production ( Figure 3).…”

“…Effector CD4 + T cells are expanded in SLE patients and produce less IL-2 and more IL-17 than CD4 + T cells in healthy controls (67). It has been shown that CREMα limits the production of IL-2 and enhances the production of IL-17 in order to expand effector T cells in SLE patients (67). Thus, CREMα alone explains the aberrant numbers of potentially pathogenic T cell subsets.…”