| Summary: | The effector programs of CD8<sup>+</sup> memory T cells are influenced by the transcription factors RUNX3, EOMES and T-bet. How these factors define brain-homing CD8<sup>+</sup> 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<sup>+</sup> T cell effector phenotypes. The frequencies of RUNX3- and EOMES-, but not T-bet-expressing CD8<sup>+</sup> 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 (<i>RUNX3</i>). RUNX3<sup>+</sup>EOMES<sup>+</sup>T-bet<sup>−</sup> CD8<sup>+</sup> 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 CD20<sup>dim</sup> and CD69<sup>+</sup> CD8<sup>+</sup> 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<sup>+</sup> memory T cells with a pre-existing brain residency-associated phenotype such that they are prone to enter the CNS in MS.
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