VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

T Schneider-Hohendorf, J Rossaint, H Mohan… - Journal of Experimental …, 2014 - rupress.org
T Schneider-Hohendorf, J Rossaint, H Mohan, D Böning, J Breuer, T Kuhlmann, CC Gross…
Journal of Experimental Medicine, 2014rupress.org
The focus of this study is the characterization of human T cell blood–brain barrier migration
and corresponding molecular trafficking signatures. We examined peripheral blood and
cerebrospinal fluid immune cells from patients under long-term anti–very late antigen-4 (VLA-
4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid
T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed
enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of …
The focus of this study is the characterization of human T cell blood–brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti–very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients’ cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients’ T cells showed increased PSGL-1–mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM+/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM+ cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood–brain barrier.
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