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

Abstract

The extravasation of CD4+ effector/memory T cells (T EM 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+ T EM 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+ T EM‐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+ T EM 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‐1 null//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.