Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier

© 2014 WILEY VCH Verlag GmbH Co. KGaA Weinheim. The extravasation of CD4+ effector/memory T cells (TEM cells) across the blood brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM 1 and ICAM 2 are essential for CD4+ TEM cell crawling on the BBB prior to diapedesis. Here we investigated the influence of cell surface levels of endothelial ICAM 1 in determining the cellular route of CD4+ TEM cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions inducing high levels of endothelial ICAM 1 promoted rapid initiation of transcellular diapedesis of CD4+ T cells across the BBB while intermediate levels of endothelial ICAM 1 favored paracellular CD4+ T cell diapedesis. Importantly the route of T cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly a low number of CD4+ TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM 1 and ICAM 2 via an obviously alternatively regulated transcellular pathway. In vivo this translated to the development of ameliorated EAE in ICAM 1null//ICAM 2 / C57BL/6J mice. Taken together our study demonstrates that cell surface levels of endothelial ICAM 1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T cell diapedesis across the BBB.