Protein phosphatase 2A facilitates IL-17 production by promoting accessibility to the IL-17 locus (47.15)

Abstract

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease caused by the combination of several immune abnormalities. T cells from SLE patients exhibit an aberrant phenotype, caused in part by increased levels of the protein phosphatase 2A (PP2A). To study the mechanisms through which PP2A alters T cell behavior and to identify the contribution of this defect to the disease, we generated a transgenic mouse that over-expresses PP2A in T cells. The transgenic mice produced abnormally high levels of IL-17A and F in vivo and in vitro. Remarkably, naïve CD4+ TPP2A cells produced IL-17 as early as 3h after stimulation. This effect was specific for IL-17 as production of type I and type II cytokines was not affected. PP2A over-expression did not promote Th17 differentiation or significant increases in Th17-related transcription factors. Due to the specificity of the phenomenon and its kinetics, we hypothesized that PP2A may facilitate transcription in the IL-17 locus. ChIP experiments revealed increased tri-methylation of H3K4 and decreased tri-methylation of H3K9 at the Il17a and Il17f promoters as well as in local conserved non-coding sequences. These changes are associated with increased chromatin accessibility. We propose that PP2A plays a central role in the transcriptional regulation of IL-17 by promoting chromatin accessibility to the IL-17 locus. This pathway may play a role in the excessive IL-17 production observed in SLE T cells.