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Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

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(+) cyto...

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Autores principales: Houston, Timothy W., Howlett-Prieto, Quentin, Regenauer, Colin, Testai, Fernando D., Yao, Faith, Feng, Xuan, Reder, Anthony T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764330/
https://www.ncbi.nlm.nih.gov/pubmed/36535763
http://dx.doi.org/10.1212/NXI.0000000000200075
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author Houston, Timothy W.
Howlett-Prieto, Quentin
Regenauer, Colin
Testai, Fernando D.
Yao, Faith
Feng, Xuan
Reder, Anthony T.
author_facet Houston, Timothy W.
Howlett-Prieto, Quentin
Regenauer, Colin
Testai, Fernando D.
Yao, Faith
Feng, Xuan
Reder, Anthony T.
author_sort Houston, Timothy W.
collection PubMed
description 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.
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spelling pubmed-97643302022-12-20 Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis Houston, Timothy W. Howlett-Prieto, Quentin Regenauer, Colin Testai, Fernando D. Yao, Faith Feng, Xuan Reder, Anthony T. Neurol Neuroimmunol Neuroinflamm Research Article 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. Lippincott Williams & Wilkins 2022-12-19 /pmc/articles/PMC9764330/ /pubmed/36535763 http://dx.doi.org/10.1212/NXI.0000000000200075 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , 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.
spellingShingle Research Article
Houston, Timothy W.
Howlett-Prieto, Quentin
Regenauer, Colin
Testai, Fernando D.
Yao, Faith
Feng, Xuan
Reder, Anthony T.
Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title_full Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title_fullStr Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title_full_unstemmed Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title_short Increased Percentage of CD8(+)CD28(−) Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis
title_sort increased percentage of cd8(+)cd28(−) regulatory t cells with fingolimod therapy in multiple sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764330/
https://www.ncbi.nlm.nih.gov/pubmed/36535763
http://dx.doi.org/10.1212/NXI.0000000000200075
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