Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression
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Updated: Jul 28, 2025
An Ex vivo Model of an Oligodendrocyte-directed T-Cell Attack in Acute Brain Slices
Published on: February 5, 2015
Ziyan Shi1, Xiaofei Wang1, Jiancheng Wang1
1Department of Neurology, West China Hospital, Sichuan University, No.28 Dianxin Nan Street, Chengdu, 610041, China.
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 + TEMRA 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 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.
Insights
Peripheral CD8+ T cells, specifically GzmB+ CD8+ TEMRA cells, are implicated in multiple sclerosis (MS) progression. Elevated GzmB+ CD8+ TEMRA cells can distinguish secondary progressive MS (SPMS) from relapsing-remitting MS (RRMS).
Area of Science:
- Immunology
- Neuroscience
- Genetics
Background:
- Multiple sclerosis (MS) involves central nervous system demyelination and neurodegeneration driven by autoimmune responses.
- Relapsing-remitting MS (RRMS) often progresses to secondary progressive MS (SPMS) in over 80% of patients, characterized by gradual neurological decline.
- Currently, no definitive treatments prevent the RRMS to SPMS transition.
Purpose of the Study:
- To investigate the role of peripheral CD8+ T cells in the RRMS to SPMS conversion.
- To identify potential diagnostic biomarkers for differentiating SPMS from RRMS.
Main Methods:
- Single-cell RNA sequencing and flow cytometry analyzed CD8+ T cell heterogeneity and dynamics in SPMS and RRMS patients.
- T cell receptor sequencing identified clonal expansion in MS.
- T-bet's role in GzmB expression was confirmed using Tbx21 siRNA; statistical models evaluated biomarker potential.
Main Results:
- SPMS patients exhibited diminished naive CD8+ T cells and increased activated CD8+ T cell subsets.
- Aberrantly amplified CD8+ T cells in SPMS showed a terminal effector (EMRA) phenotype with GzmB expression and distinct clonal expansion.
- GzmB expression in CD8+ T cells correlated positively with MS disability and progression, accurately distinguishing SPMS from RRMS.
Conclusions:
- Peripheral GzmB+ CD8+ TEMRA cells are involved in MS progression.
- These cells serve as a potential diagnostic biomarker for differentiating SPMS from RRMS.
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