Exhausted Regulatory CD4⁺ T Cells Identified in Lupus via Single-Cell Analysis

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Summary

The team delved into the intricacies of systemic lupus erythematosus (SLE), a persistent autoimmune disorder. They scrutinized CD4⁺ T cell variations and their ties to SLE onset using ATAC-seq and scRNA-seq on cells from 72 SLE sufferers and 30 unaffected individuals. Discoveries indicated that chromatin patterns in these cells align with disease intensity. Analyzing over 34,000 transcriptomes, they pinpointed anomalies in regulatory T cells, highlighting two specific subgroups. One, the CCR7lowCD74hi subgroup, showed signs of type I interferon-driven exhaustion in SLE individuals. Their data sheds light on uncharted areas of SLE development, emphasizing the role of weary regulatory T cells.

Fig.1 Graphical abstract¹.

Research Criteria

The study focuses on systemic lupus erythematosus (SLE), a chronic autoimmune disease, and the role of CD4⁺ T cells in promoting SLE development. The researchers performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and single-cell transcriptome sequencing (scRNA-seq) on peripheral CD4⁺ T cells from 72 SLE patients and 30 healthy controls.

Sample Type

The samples used for the single-cell experiments were peripheral CD4⁺ T cells from 72 SLE patients and 30 healthy controls.

Result—Chromatin Accessibility Profiles in CD4⁺ T Cells from Healthy Controls and SLE Patients

Researchers generated 102 high-resolution ATAC-seq profiles from cells freshly isolated from both healthy individuals and SLE patients. The dataset encompassed 65 samples from 63 SLE patients, with detailed clinical information, and 37 samples from 25 healthy controls. Notably, a significant portion of the SLE cohort was newly diagnosed, with many exhibiting severe disease activities. The ATAC-seq analysis identified over 103,000 high-quality peaks of DNA accessibility in both healthy and SLE CD4⁺ T cells, confirming the validity of the study. The data revealed distinct chromatin accessibility patterns around key genes, such as CD3D and CD4, and demonstrated that the sample size was adequately large to capture most DNA accessible sites in these cells. This research provides a robust genome-wide chromatin accessibility profile, shedding light on the differences between healthy individuals and those with SLE at the chromatin level.

Fig.2 Heterogeneity in DNA accessibility within peripheral CD4⁺ T cells in SLE patients¹.

Result—Severe-Stage SLE Patients' Single-Cell Atlas of CD4⁺ T Cells

Researchers conducted an in-depth analysis of CD4⁺ T cells from severe-stage SLE (Systemic Lupus Erythematosus) patients, revealing the heterogeneity and distinct subtypes within this cell population. Using the 10X platform for single-cell RNA sequencing (scRNA-seq), they analyzed CD4⁺ T cells from both SLE patients and healthy controls. Post quality control, they identified 16 distinct clusters of CD4⁺ T cell subtypes. Seven major subtypes were recognized, including naive T cells (CCR7+ Tn), T helper cells (Th1, Th2, Th17), regulatory T cells (FOXP3+ Treg), and cytotoxic CD4⁺ T cells (GNLY+ Tct). Notably, SLE patients exhibited a decreased proportion of naive CD4⁺ T cells and an increased proportion of effector and regulatory T cells compared to healthy individuals. This comprehensive single-cell atlas offers valuable insights into the cellular dynamics of CD4⁺ T cells in SLE, highlighting the potential role of specific T cell subtypes in the disease's pathogenesis.

Fig.3 Comprehensive single-cell atlas of peripheral CD4⁺ T cells: normal vs. SLE patients¹.

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Reference

1. Guo, Chuang, et al. "Single-cell transcriptome profiling and chromatin accessibility reveal an exhausted regulatory CD4⁺ T cell subset in systemic lupus erythematosus." Cell Reports 41.6 (2022).