Abstract
Background and Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. CD8+ T cells are prominently found at inflammatory sites. Recent advances in understanding checkpoint molecules, including programmed cell death 1 (PD-1), expressed on CD8+ T cells, highlight the immune regulatory roles of this T-cell subset; however, the role of CD8+ T cells in MS is unclear. Thus, we aimed to reveal the characteristics of PD-1–expressed (PD-1+) CD8+ T cells in MS.
Methods We performed a cohort, case-control study for phenotyping analysis of PD-1+CD8+ T cells in disease remission and flare states using CSF and peripheral blood samples of 45 patients with MS or clinically isolated syndrome and 12 healthy subjects. We further analyzed the transcriptome of sorted PD-1+CD8+ T cells obtained from interferon (IFN)-β–treated patients and validated their regulatory machinery using in vitro cell culture assays with lentiviral gene transfer.
Results In the disease remission state, PD-1+CD8+ T cells were decreased in the peripheral blood of patients with MS and resolved in patients treated with IFN-β treatment who showed immune regulatory cytokine interleukin (IL)-10 expression. In the disease flare state, we found that PD-1+CD8+ T cells were enriched in the CSF, which predicted a good response to subsequent IV steroid therapy. Transcriptome analysis of sorted PD-1+CD8+ T cells revealed the transcription factor c-Maf as a potential major regulator of the gene module, including multiple coinhibitory molecules. Furthermore, c-Maf expressed in CD8+ T cells induced PD-1 expression and production of IL-10 as well as suppressed alloactivated CD4+ T-cell survival.
Discussion This study uncovered a favorable role of PD-1+CD8+ T cells against MS and demonstrated that c-Maf–driven IL-10 is an immune regulatory machinery.
Glossary
- ANOVA=
- analysis of variance;
- CIS=
- clinically isolated syndrome;
- DE=
- differentially expressed;
- EAE=
- experimental autoimmune encephalomyelitis;
- EDSS=
- Expanded Disability Status Scale;
- FACS=
- fluorescence-activated cell sorting;
- HS=
- healthy subject;
- IFN=
- interferon;
- IL=
- interleukin;
- IVMP=
- IV methylprednisolone;
- MLR=
- mixed lymphocyte reaction;
- MS=
- multiple sclerosis;
- PBMC=
- peripheral blood mononuclear cell;
- PD-L1=
- PD-1 ligand 1;
- qRT-PCR=
- quantitative real-time PCR
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
- Received July 12, 2021.
- Accepted in final form February 28, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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