Single-cell transcriptome profiling and chromatin accessibility reveal an exhausted regulatory CD4+ T cell subset in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, and CD4⁺ T cells are known to promote SLE development. Here, we explore heterogeneities in the CD4⁺ T cell regulome and their associations with SLE pathogenesis by performing assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and single-cell transcriptome sequencing (single-cell RNA sequencing [scRNA-seq]) of peripheral CD4⁺ T cells from 72 SLE patients and 30 healthy controls. Chromatin accessibility signatures of CD4⁺ T cells are correlated with disease severity. Further, we generate 34,176 single-cell transcriptomes of healthy and SLE CD4⁺ T cells and reveal transcriptional dysfunction of regulatory T (Treg) cells, identifying two Treg subpopulations, among which the CCR7^lowCD74^hi Treg subgroup features type I interferon-induced functional exhaustion in SLE patients. These transcriptome-level findings for SLE Tregs are mirrored in trends from the ATAC-seq data. Our study establishes a rich empirical foundation for understanding SLE and uncovers previously unknown contributions of Treg with exhaustion-like properties to SLE pathogenesis.