Regulation of CXCL12 and CXCR4 expression by human brain endothelial cells and their role in CD4+ and CD8+ T cell adhesion and transendothelial migration

Abstract 

Chemokines have emerged as important mediators of leukocyte recruitment to the CNS across the normally restrictive blood–brain barrier (BBB). In the present study we investigated the regulation of CXCL12 and its receptor, CXCR4, expression in human brain microvessel endothelial cells (HBMEC) and the effects of CXCL12 on the adhesion and migration of CD4+ and CD8+ T lymphocytes across HBMEC monolayers. Resting HBMEC constitutively expressed CXCL12 and CXCR4. Treatment with TNF-α, IFN-γ, IL-1β and LPS downregulated CXCL12 and CXCR4 expression and CXCL12 ligation induced internalization of CXCR4. The minimal adhesion and migration of CD4+ and CD8+ T lymphocytes across resting HBMEC were increased following cytokine treatment of HBMEC. CXCL12 gradients further enhanced adhesion of both T cell subsets to activated HBMEC and migration across resting monolayers. A greater number of CD8+ T lymphocytes adhered and migrated across activated HBMEC compared to CD4+ T cells. These studies provide insight into the regulation of CXCL12 and CXCR4 expression in cerebral EC and indicate an important role for CXCL12 in T cell subset recruitment across the BBB in CNS inflammation.

Keywords: Blood–brain barrier, Cytokines, T cell trafficking, CXCL12, CXCR4, Neuroinflammation