Distinct Effector Programs of Brain-Homing CD8+ T Cells in Multiple Sclerosis

Steven C. Koetzier, Jamie van Langelaar, Marie José Melief, Annet F. Wierenga-Wolf, Cato E.A. Corsten, Katelijn M. Blok, Cindy Hoeks, Bieke Broux, Beatrijs Wokke, Marvin M. van Luijn*, Joost Smolders*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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Abstract

The effector programs of CD8+ memory T cells are influenced by the transcription factors RUNX3, EOMES and T-bet. How these factors define brain-homing CD8+ memory T cells in multiple sclerosis (MS) remains unknown. To address this, we analyzed blood, CSF and brain tissues from MS patients for the impact of differential RUNX3, EOMES and T-bet expression on CD8+ T cell effector phenotypes. The frequencies of RUNX3-and EOMES-, but not T-bet-expressing CD8+ memory T cells were reduced in the blood of treatment-naïve MS patients as compared to healthy controls. Such reductions were not seen in MS patients treated with natalizumab (anti-VLA-4 Ab). We found an additional loss of T-bet in RUNX3-expressing cells, which was associated with the presence of MS risk SNP rs6672420 (RUNX3). RUNX3+EOMES+T-bet CD8+ memory T cells were enriched for the brain residency-associated markers CCR5, granzyme K, CD20 and CD69 and selectively dominated the MS CSF. In MS brain tissues, T-bet coexpression was recovered in CD20dim and CD69+ CD8+ T cells, and was accompanied by increased coproduction of granzyme K and B. These results indicate that coexpression of RUNX3 and EOMES, but not T-bet, defines CD8+ memory T cells with a pre-existing brain residency-associated phenotype such that they are prone to enter the CNS in MS.

Original languageEnglish
Article number1634
JournalCells
Volume11
Issue number10
DOIs
Publication statusPublished - 13 May 2022

Bibliographical note

Funding: This study was funded by the Dutch MS Research Foundation (15-490d MS, 16-952 MS, 19-1075 MS and 20-490f MS).

Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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