Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression

Ziyan Shi; Xiaofei Wang; Jiancheng Wang; Hongxi Chen; Qin Du; Yanlin Lang; Lingyao Kong; Wenqin Luo; Yuhan Qiu; Ying Zhang; Chen Li; Dingke Wen; Jie Yao; Xia Cheng; Linjun Cai; Xue Lin; Rui Wang; Zichao Mou; Shuangjie Li; Duanya Liu; Hong Zhou; Hongyu Zhou; Mu Yang

doi:10.1186/s12974-023-02810-0

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression

J Neuroinflammation. 2023 Jun 2;20(1):138. doi: 10.1186/s12974-023-02810-0.

Authors

Ziyan Shi^#¹, Xiaofei Wang^#¹, Jiancheng Wang¹, Hongxi Chen¹, Qin Du¹, Yanlin Lang¹, Lingyao Kong¹, Wenqin Luo¹, Yuhan Qiu¹, Ying Zhang¹, Chen Li^{2

3}, Dingke Wen⁴, Jie Yao², Xia Cheng², Linjun Cai¹, Xue Lin¹, Rui Wang¹, Zichao Mou¹, Shuangjie Li¹, Duanya Liu³, Hong Zhou⁵, Hongyu Zhou⁶, Mu Yang^{7

8}

Affiliations

¹ Department of Neurology, West China Hospital, Sichuan University, No.28 Dianxin Nan Street, Chengdu, 610041, China.
² Centre for Translational Research in Cancer, Sichuan Cancer Hospital and Institute, No.55 South Renmin Road, Chengdu, 610000, China.
³ School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China.
⁴ Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
⁵ School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610000, China.
⁶ Department of Neurology, West China Hospital, Sichuan University, No.28 Dianxin Nan Street, Chengdu, 610041, China. zhouhy@scu.edu.cn.
⁷ Centre for Translational Research in Cancer, Sichuan Cancer Hospital and Institute, No.55 South Renmin Road, Chengdu, 610000, China. mu.yang@uestc.edu.cn.
⁸ School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China. mu.yang@uestc.edu.cn.

^# Contributed equally.

Abstract

Background: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS.

Methods: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively.

Results: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + T_EMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy.

Conclusions: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + T_EMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Keywords: CD8 + TEMRA cells; Clonal expansion; GzmB; Multiple sclerosis; Secondary progression; Single-cell RNA sequencing.

MeSH terms

CD8-Positive T-Lymphocytes
Granzymes
Humans
Multiple Sclerosis* / diagnosis
Multiple Sclerosis, Chronic Progressive* / diagnosis
Multiple Sclerosis, Relapsing-Remitting* / diagnosis
T-Lymphocyte Subsets

Substances

Granzymes

Abstract

MeSH terms

Substances

Grants and funding