Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares.

A total of 74 lupus patients with an SLE Disease Activity Index score of 0–18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome‐wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays.

We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA‐26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients.

An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non‐Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.