Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423000725 |
| _version_ | 1811158417686921216 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hui Xiong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T05:23:11Z |
| format | Article |
| id | doaj.art-06ef090c1532479494a64f8f0ea5497a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-10T05:23:11Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-06ef090c1532479494a64f8f0ea5497a2023-03-08T04:14:28ZengElsevierEBioMedicine2352-39642023-04-0190104507Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in contextHui Xiong0Mintian Cui1Ni Kong2Jiongjie Jing3Ying Xu4Xiuting Liu5Fan Yang6Zhen Xu7Yu Yan8Dongyang Zhao9Ziqi Zou10Meng Xia11Junjie Cen12Guozhen Tan13Cong Huai14Qiong Fu15Qing Guo16Kun Chen17Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaDepartment of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaTranslational Medical Center for Stem Cell Therapy, Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200127, ChinaDepartment of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, ChinaInstitute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, ChinaInstitute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, ChinaBio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, ChinaDepartment of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, 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; 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.http://www.sciencedirect.com/science/article/pii/S2352396423000725Systemic lupus erythematosusscRNA-seqWhole-exome sequencingCD8+ T cell subsetGenetic variantDTHD1 |
| spellingShingle | 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 Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context EBioMedicine Systemic lupus erythematosus scRNA-seq Whole-exome sequencing CD8+ T cell subset Genetic variant DTHD1 |
| title | Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context |
| title_full | Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context |
| title_fullStr | Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context |
| title_full_unstemmed | Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context |
| title_short | Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosusResearch in context |
| title_sort | cytotoxic cd161 cd8 temra cells contribute to the pathogenesis of systemic lupus erythematosusresearch in context |
| topic | Systemic lupus erythematosus scRNA-seq Whole-exome sequencing CD8+ T cell subset Genetic variant DTHD1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423000725 |
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