Increased Percentage of CD8+CD28− Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
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Abstract
Background and Objectives Fingolimod, an oral therapy for MS, decreases expression of membrane S1P1 receptors on CD4+ memory cells, causing their retention and deactivation in lymph nodes. We determined fingolimod effects on the number and proportion of potentially CNS-damaging CD8+CD28+ cytolytic T lymphocyte cells (CTLs) and on MS-depleted and dysfunctional CD8+CD28− anti-inflammatory suppressor/regulatory T cells (Treg) and on CD8+ T-cell expression of the CD69 activation/lymph node retention protein in MS.
Methods CD8, CD28, CD4, and CD69 expression on peripheral blood mononuclear cells was measured with flow cytometry. In vitro concanavalin A (ConA) activation of T cells, including CD8+CD28− cells, was used to mimic inflammation.
Results Fifty-nine patients with MS, 35 therapy-naive (16 clinically stable; 19 exacerbating) and 24 fingolimod-treated (19 clinically stable; 5 exacerbating), and 26 matched healthy controls (HCs) were compared. In therapy-naive patients, the CD8+ Treg percent of total lymphocytes was only 1/4 of HC levels. In fingolimod-treated patients, however, CD8+ Treg percentages rose to 2.5-fold higher than in HC and 10-fold higher than in therapy-naive MS. With fingolimod therapy, in contrast, CD8+ CTL levels were less than half of levels in HCs and therapy-naive patients. In HCs and all MS, activation with ConA strongly induced CD69 expression on CD4+ cells and induced 3-fold higher CD69 levels on CD8+ CTL than on CD8+ Treg. Fingolimod and analogs in vitro did not modify lymphocyte CD69 expression. Lower levels of CD69 on CD8+ Treg than on CTL may allow easier Treg egress from lymph nodes and enhance control of peripheral inflammation. In vitro activation reduced the already low CD8+ Treg population in therapy-naive MS, but only slightly altered Treg levels in fingolimod-treated MS.
Discussion Fingolimod therapy markedly increases the percentage of CD8+ Treg in MS, reversing the low CD8+ Treg:CTL ratio seen in untreated MS. The increase in immune regulatory cells has potential therapeutic benefit in MS. Activation in vitro depletes CD8+CD28+CTL in patients with MS; the loss is more pronounced in older patients with MS. This suggests that inflammation can disrupt the tenuous immune regulation in MS, especially in older patients.
Glossary
- B=
- Black/African ancestry;
- ConA=
- Concanavalin A mitogen;
- CTL=
- Cytolytic T lymphocyte;
- DNS=
- Data not shown;
- EDSS=
- Extended disability scale score of Kurtzke;
- F=
- Female;
- FTY=
- Fingolimod/FTY720;
- FTY-p=
- FTY-phosphate;
- H=
- Hispanic;
- HC=
- healthy control;
- I=
- Indian/South Asian;
- M=
- Male;
- MFI=
- Median fluorescence intensity;
- MS-a=
- Active/exacerbating MS;
- MS-s=
- Clinically stable MS;
- N=
- Number;
- NA=
- Not applicable;
- NS=
- Not significant;
- O=
- Other (East Asian ancestry);
- PBMC=
- Peripheral blood mononuclear cell;
- PPMS=
- Progressive forms of MS;
- RRMS=
- Stable relapsing/remitting MS;
- Rx=
- Treatment;
- S1PR=
- Sphingosine 1-phosphate receptor;
- SEM=
- Standard error of the mean;
- SPMS=
- Secondary Progressive form of MS;
- Treg=
- Regulatory T cell;
- W=
- White/Caucasian
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.
Submitted and externally peer reviewed. The handling editor was Scott S. Zamvil, MD, PhD, FAAN.
- Received June 9, 2022.
- Accepted in final form October 20, 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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