MCAM+ brain endothelial cells contribute to neuroinflammation by recruiting pathogenic CD4+ T lymphocytes.

The trafficking of autoreactive leukocytes across the blood-brain barrier (BBB) endothelium is a hallmark of multiple sclerosis (MS) pathogenesis. Although the BBB endothelium represents one of the main central nervous system (CNS) borders to interact with the infiltrating leukocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells (ECs) with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis (EAE). In addition, MCAM was preferentially upregulated on BBB ECs in MS lesions in situ and at EAE disease onset by molecular magnetic resonance imaging. In vitro and in vivo, we demonstrate that MCAM on BBB ECs contributes to EAE development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the BBB. Lastly, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the BBB in vitro, in vivo and in MS lesions as detected by flow cytometry on rapid autopsy derived brain tissue from MS patients. Collectively, our findings reveal that MCAM is at the center of a pathological pathway used by brain ECs to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat MS.