The mechanisms that govern whether T cells cross blood-brain barrier (BBB) endothelium by transcellular versus paracellular routes are unclear. Caveolin-1 is a membrane scaffolding and signaling protein associated with transcellular transmigration through the endothelial cytoplasm. Here, we report that the neuroinflammatory chemokine CXCL10 induced transcellular, caveolar transmigration of CXCR3+ CD4+ T cells. Specifically, data revealed that CXCL10-induced transcellular transmigration requires expression of Caveolin-1 and ICAM-1 in brain endothelial cells and of the CXCL10 receptor, CXCR3, and LFA-1 in T cells. Moreover, Caveolin-1 promoted CXCL10 aggregation into brain endothelial cytoplasmic stores, providing a mechanism for activation and recruitment of CXCR3+ T cells to migrate at cytoplasmic locations, distal to cell-cell junctions. Consistent with our in vitro data, genetic ablation of Caveolin-1 reduces infiltration of CXCR3+ CD4+ T cells into the CNS in experimental autoimmune encephalomyelitis. Our findings establish a novel mechanism by which brain endothelial cells utilize Caveolin-1 dependent CXCL10 intracellular stores to license T cells for transcellular migration across the blood-brain barrier.
Keywords: CD4; CXCL10; Caveolin-1; blood-brain barrier; experimental autoimmune encephalomyelitis; transendothelial migration.
The neuroinflammatory chemokine CXCL10 specifically promotes transcellular, rather than paracellular, CD4+ T cell transmigration across brain endothelial cellsBrain endothelial cell Caveolin-1 is required for CXCL10-induced transcellular CD4+ T cell migrationBrain endothelial cell Caveolin-1 promotes aggregation of CXCL10 into cytoplasmic storesCNS infiltration of CD4+ T cells expressing the CXCL10 receptor, CXCR3 is reduced in Caveolin-1 null mice in the EAE model.