# Angiotensin receptor blockers modulate the lupus CD4+ T cell epigenome characterized by TNF family–linked signaling

## TL;DR

This study shows that CD4+ T cells in lupus patients have epigenetic changes linked to TNF family signals, which can be modulated by angiotensin receptor blockers.

## Contribution

The study identifies a novel link between ARBs and modulation of lupus-related epigenetic changes in CD4+ T cells.

## Key findings

- Lupus patients show increased chromatin accessibility linked to inflammatory cytokine signals in CD4+ T cells.
- Naive CD4+ T cells are uniformly affected by chromatin changes associated with TNF family members like TNF-α, LIGHT, and TWEAK.
- Patients taking ARBs lack TNF-linked chromatin changes, suggesting a potential therapeutic role for these drugs.

## Abstract

In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from patients with lupus and healthy individuals. Most patients with lupus, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single-cell approaches revealed that chromatin changes extended to naive CD4+ T cells, uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNF-α, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs), which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.

CD4+ T cells in lupus have TNF family-associated epigenetic changes that may be modulated by angiotensin receptor blockers