Pathways Across The Blood-Brain Barrier

The parenchymal blood-brain barrier (BBB) is formed by highly specialized vascular endothelial cells of the central nervous system (CNS). As part of the neurovascular unit (NVU), the BBB builds up a tight barrier between the changing milieu of the bloodstream and the vulnerable CNS. Yet, during inflammatory diseases of the CNS, immune cells are recruited into the CNS and thus migrate across the inflamed BBB. In particular, effector T (T-eff) cells critically contribute to autoimmune neuroinflammation such as multiple sclerosis (MS). Extravasation of T-eff cells across the inflamed BBB is a well-coordinated multistep process tightly regulated through cell adhesion molecules, chemotactic factors, and their receptors. An initial contact between the circulating T-eff cell and the inflamed endothelial cells of the BBB mediates slowing down of T-eff cells. Then, integrins on the T-eff cell surface acquire an activated conformation. This in turn is prerequisite for shear-resistant arrest that transforms into firm adhesion, crawling, and finally diapedesis. Following diapedesis, T-eff cells accumulate in the perivascular space between the two basement membranes of the NVU. Only after reactivation with their cognate antigen by antigen- presenting cells (APCs), T-eff cells can breach the parenchymal basement membrane and infiltrate the CNS parenchyma. Interfering with pathological T-eff cell recruitment into the CNS has been successfully translated into the clinic for the treatment of MS patients through natalizumab, which blocks extravasation of immune cells across the BBB. This review introduces the molecular players and discusses the cellular pathway of T-eff cell extravasation across the inflamed BBB.