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 SLEdevelopment. Here, we explore heterogeneities in theCD4(+) 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(low)CD74(hi) Treg subgroup features type I interferon-induced functional exhaustion in SLEpatients. These transcriptome-level findings forSLETregs are mirrored in trends from theATAC-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.