Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus

Johanna Breuer,Tilman Schneider-Hohendorf,Ken Flanagan,Heinz Wiendl,Eva Korpos,Lisa Zondler,Thomas Korn,Alexander Zarbock,Nicholas Schwab,Melanie-Jane Hannocks,Sebastian Herich,Jian Song,Tanja Kuhlmann,Lydia Sorokin

doi:10.1186/s12974-018-1276-4

Abstract

BackgroundVery late antigen 4 (VLA-4; integrin α4β1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previously shown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migration of human TH17 cells in vitro and here investigate their contribution to pathogenic CNS inflammation.MethodsAntibody blockade of VLA-4 and MCAM is assessed in murine models of CNS inflammation in conjunction with conditional ablation of α4-integrin expression in T cells. Effects of VLA-4 and MCAM blockade on lymphocyte migration are further investigated in the human system via in vitro T cell transmigration assays.ResultsCompared to the broad effects of VLA-4 blockade on encephalitogenic T cell migration over endothelial barriers, MCAM blockade impeded encephalitogenic T cell migration in murine models of MS that especially depend on CNS migration across the choroid plexus (CP). In transgenic mice lacking T cell α4-integrin expression (CD4::Itga4−/−), MCAM blockade delayed disease onset. Migration of MCAM-expressing T cells through the CP into the CNS was restricted, where laminin 411 (composed of α4, β1, γ1 chains), the proposed major ligand of MCAM, is detected in the endothelial basement membranes of murine CP tissue. This finding was translated to the human system; blockade of MCAM with a therapeutic antibody reduced in vitro transmigration of MCAM-expressing T cells across a human fibroblast-derived extracellular matrix layer and a brain-derived endothelial monolayer, both expressing laminin α4. Laminin α4 was further detected in situ in CP endothelial-basement membranes in MS patients’ brain tissue.ConclusionsOur findings suggest that MCAM-laminin 411 interactions facilitate trans-endothelial migration of MCAM-expressing T cells into the CNS, which seems to be highly relevant to migration via the CP and to potential future clinical applications in neuroinflammatory disorders.

Highlights

Very late antigen 4 (VLA-4; integrin α4β1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS)
Apart from leukocyte function-associated molecule-1 (LFA-1)–intercellular adhesion molecule-1 (ICAM-1)-dependent penetration of the choroid plexus (CP) by TH17 cells, we have recently shown that adhesion of TH17 cells to an in vitro model of the blood-brain barrier (BBB) in the absence of VLA-4 involves melanoma cell adhesion molecule (MCAM; CD146) [17]
TH17 cells are further able to access the CNS parenchyma independently of VLA-4 and MOG35–55 immunized mice lacking α4-integrin expression on T cells (CD4::Itga4−/−) exhibit marked immune cell infiltration within the plexus epithelium [12], indicating that in the absence of α4-integrin encephalitogenic T cells are recruited via the choroid plexus into the CNS

Summary

Introduction

Very late antigen 4 (VLA-4; integrin α4β1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). VLA-4 plays a key role in the entry of encephalitogenic T cells into the CNS by mediating the initial rolling and adhesion steps of transmigration through interaction with its receptor, vascular cell adhesion molecule-1 (VCAM-1), expressed on Breuer et al Journal of Neuroinflammation (2018) 15:236 endothelial cells of post-capillary venules upon inflammation [7]. LFA-1 is primarily involved in the firm adhesion to endothelium and subsequent para-endothelial migration, and not in the initial rolling and adhesive steps [14] This poses the question of how the initial adhesive steps are mediated in the encephalitogenic TH17 subpopulation and raises the possibility that different immune cell-adhesion receptor interactions are employed, depending on the route of entry into the brain and the cellular barrier involved. Three important barriers restrict access of circulating immune cells to the CNS parenchyma: the endothelial BBB in CNS post-capillary venules, the epithelial-cerebrospinal fluid barrier (BCSFB) at the CP, and the arachnoidea formed by leptomeningeal cells [14,15,16]

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Conclusion