OR.18. VLA-4-Dependent Recruitment of Effector Memory CD8+T Lymphocytes into the Central Nervous System

The presence of CD8⁺T lymphocytes in infiltrates of the central nervous systems (CNS) has been well documented: clonally expanded CD8⁺T lymphocytes are present in multiple sclerosis (MS) lesions, as well as in the cerebrospinal fluid (CSF) of MS patients. In human MS, and in its animal model Experimental Autoimmune Encephalomyelitis (EAE), CD8⁺T lymphocytes are found in active lesions. However the phenotype of migrating CD8⁺T lymphocytes and the mechanism by which such cells cross the blood-brain barrier (BBB) remains largely unknown. Using CSF obtained from MS patients and spinal cord material from myelin MOG_(35-55)-induced EAE and from coronavirus-induced encephalitis, we demonstrate that CD8⁺T lymphocytes are mostly of the effector memory (EM) phenotype (CD8⁺, CD62L^-, CCR7^-, CD28^-, GranzymeB^hi). We further show that purified human CD8⁺TEM lymphocytes transmigrate more readily across human BBB endothelial cells than ex vivo un-fractionated CD8 lymphocytes and that BBB endothelium promotes the selective recruitment of CD8⁺TEM lymphocytes. Furthermore, we provide evidence for an active and selective recruitment of IFN-γ-and IL-17-secreting CD8⁺lymphocytes by human and mouse BBB endothelium, in vitro and in vivo. Finally we show that the migration of CD8⁺T lymphocytes across BBB-ECs is dependent on VLA-4, but independent of ICAM-1/LFA-1, ALCAM and the chemokine MCP-1. Our study thus provides evidence for an active role of the BBB in the recruitment of potentially auto-aggressive IL-17 and IFN-γ secreting CD8 TEM lymphocytes to the CNS, through a VCAM-1/VLA-4 adhesion molecule pathway.