Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosus

作者：Hui Xiong, Mintian Cui, Ni Kong, Jiongjie Jing, Ying Xu, Xiuting Liu, Fan Yang, Zhen Xu, Yu Yan, Dongyang Zhao, Ziqi Zou, Xia Meng, Junjie Cen, Guozhen Tan, Cong Huai, Qiong Fu, Qing Guo, Kun Chen · 发表于：EBioMedicine · 年份：2023 · DOI：10.1016/j.ebiom.2023.104507 · 被引用次数：45 · 研究领域：Cell Adhesion Molecules Research、Phagocytosis and Immune Regulation、T-cell and B-cell Immunology

Background Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8 + T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8 + T cells in SLE remain to be identified. Methods Single-cell RNA sequencing (scRNA-seq) of PBMCs from a SLE family pedigree (including 3 HCs and 2 SLE patients) was performed to identify the SLE-associated CD8 + T cell subsets. Flow cytometry analysis of a SLE cohort (including 23 HCs and 33 SLE patients), qPCR analysis of another SLE cohort (including 30 HCs and 25 SLE patients) and public scRNA-seq datasets of autoimmune diseases were employed to validate the finding. Whole-exome sequencing (WES) of this SLE family pedigree was used to investigate the genetic basis in dysregulation of CD8 + T cell subsets identified in this study. Co-culture experiments were performed to analyze the activity of CD8 + T cells. Findings We elucidated the cellular heterogeneity of SLE and identified a new highly cytotoxic CD8 + T cell subset, CD161 − CD8 + T EMRA cell subpopulation, which was remarkably increased in SLE patients. Meanwhile, we discovered a close correlation between mutation of DTHD1 and the abnormal accumulation of CD161 − CD8 + T EMRA cells in SLE. DTHD1 interacted with MYD88 to suppress its activity in T cells and DTHD1 mutation promoted MYD88-dependent pathway and subsequently increased the ...