Lymphocyte adhesion and subsequent trafficking across endothelial barriers are essential steps in various immune-mediated disorders of the central nervous system (CNS), including multiple sclerosis (MS). The molecular mechanisms underlying these processes, however, are still unknown. Phospholipase D1 (PLD1), an enzyme that generates phosphatidic acid through hydrolysis of phosphatidylcholine and additionally yields choline as a product, has been described as regulator of the cell mobility. By using PLD1-deficient mice we investigated the functional significance of PLD1 for lymphocyte adhesion and migration in vitro and after MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a model of human MS. The lack of PLD1 reduced chemokine-mediated static adhesion of lymphocytes to the endothelial adhesion molecules VCAM-1 and ICAM-1 in vitro, and was accompanied by a decreased migratory capacity in both blood brain barrier and cell migration models. Importantly, PLD1 is also relevant for the recruitment of immune cells into the CNS in vivo since disease severity after EAE was significantly attenuated in PLD1-deficient mice. Furthermore PLD1 expression could be detected on lymphocytes in MS patients. Our findings suggest a critical function of PLD1-dependent intracellular signaling cascades in regulating lymphocyte trafficking during autoimmune CNS inflammation.This article is protected by copyright. All rights reserved