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

doi:10.3390/cells11101634

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

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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.

Originele taal-2	Engels
Artikelnummer	1634
Tijdschrift	Cells
Volume	11
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.3390/cells11101634
Status	Gepubliceerd - 13 mei 2022

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10.3390/cells11101634

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@article{59e074432464478cb18282e14685daf8,

title = "Distinct Effector Programs of Brain-Homing CD8+ T Cells in Multiple Sclerosis",

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-na{\"i}ve 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.",

author = "Koetzier, {Steven C} and {van Langelaar}, Jamie and Marie-Jos{\'e} Melief and Wierenga-Wolf, {Annet F} and Corsten, {Cato E A} and Blok, {Katelijn M} and Cindy Hoeks and Bieke Broux and Beatrijs Wokke and {van Luijn}, {Marvin M} and Joost Smolders",

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AU - Koetzier, Steven C

AU - van Langelaar, Jamie

AU - Melief, Marie-José

AU - Wierenga-Wolf, Annet F

AU - Corsten, Cato E A

AU - Blok, Katelijn M

AU - Hoeks, Cindy

AU - Broux, Bieke

AU - Wokke, Beatrijs

AU - van Luijn, Marvin M

AU - Smolders, Joost

PY - 2022/5/13

Y1 - 2022/5/13

N2 - 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.

AB - 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.

U2 - 10.3390/cells11101634

DO - 10.3390/cells11101634

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SN - 2073-4409

VL - 11

JO - Cells

JF - Cells

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ER -

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

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