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

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the central nervous system (CNS). CD4 + T cells are assumed to be the first to cross the blood-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 an 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. This article is protected by copyright. All rights reserved.