Differential Runx3, Eomes, and T‐bet expression subdivides MS‐associated CD4 ⁺ T cells with brain‐homing capacity

Abstract

Abstract Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity‐associated effector programs define CD4 + T cell subsets with brain‐homing ability in MS. Runx3‐ and Eomes‐, but not T‐bet‐expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 + Eomes + T‐bet − enrichment in cerebrospinal fluid samples of treatment‐naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 + CXCR3 + CCR4 −/dim ). Previously published CD28 − CD4 T cells were characterized by a Runx3 + Eomes − T‐bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady‐state conditions, granzyme K high Th17.1 cells spontaneously passed the blood–brain barrier in vitro . This was only found for other subsets including CD28 − cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS.