CAMP response element modulator ? 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)? contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREM? also reduces CpG-DNA methylation of the IL17A promoter. CREM? expression is regulated at the epigenetic level by CpG-DNA methylation, which allows increased CREM? expression in effector memory CD4(+) T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREM? 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 CREM? mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease.

SUBMITTER: Hedrich CM 

PROVIDER: S-EPMC3478624 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature