Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context
Hui Xiong,
Mintian Cui,
Ni Kong,
Jiongjie Jing,
Ying Xu,
Xiuting Liu,
Fan Yang,
Zhen Xu,
Yu Yan,
Dongyang Zhao,
Ziqi Zou,
Meng Xia,
Junjie Cen,
Guozhen Tan,
Cong Huai,
Qiong Fu,
Qing Guo,
Kun Chen
Affiliations
Hui Xiong
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
Mintian Cui
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Ni Kong
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Jiongjie Jing
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Ying Xu
Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
Xiuting Liu
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
Fan Yang
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Zhen Xu
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Yu Yan
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China
Dongyang Zhao
Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Ziqi Zou
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China
Meng Xia
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China
Junjie Cen
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
Guozhen Tan
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
Cong Huai
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China
Qiong Fu
Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
Qing Guo
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Corresponding author.
Kun Chen
Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China; Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China; Corresponding author. Translational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, China.
Summary: 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+ TEMRA 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+ TEMRA 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 proliferation and cytotoxicity of CD161−CD8+ TEMRA cells. Furthermore, the differentially expressed genes in CD161−CD8+ TEMRA cells displayed a strong out-of-sample prediction for case–control status of SLE. Interpretation: This study identified DTHD1-associated expansion of CD161−CD8+ TEMRA cell subpopulation is critical for SLE. Our study highlights genetic association and cellular heterogeneity of SLE pathogenesis and provides a mechanistical insight into the diagnosis and treatment of SLE. Fundings: Stated in the Acknowledgements section of the manuscript.
