Distinct Effector Programs of Brain-Homing CD8<sup>+</sup> 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
Affiliations
Steven C. Koetzier
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Jamie van Langelaar
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Marie-José Melief
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Annet F. Wierenga-Wolf
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Cato E. A. Corsten
MS Center ErasMS, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Katelijn M. Blok
MS Center ErasMS, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Cindy Hoeks
Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium
Bieke Broux
Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium
Beatrijs Wokke
MS Center ErasMS, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Marvin M. van Luijn
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
Joost Smolders
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3000 Rotterdam, The Netherlands
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.
