Published online before print August 20, 2009

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(Journal of Leukocyte Biology. 2009;86:1049-1063.)
© 2009 Society for Leukocyte Biology

Peripheral blood CD4+ T lymphocytes from multiple sclerosis patients are characterized by higher PSGL-1 expression and transmigration capacity across a human blood-brain barrier-derived endothelial cell line

Bouchaib Bahbouhi^*, Laureline Berthelot^*, Ségolène Pettré^*, Laure Michel^*, Sandrine Wiertlewski, Babette Weksler, Ignacio-Andres Romero, Florence Miller^||, Pierre-Olivier Couraud^||, Sophie Brouard^*, David-Axel Laplaud^*,,1 and Jean-Paul Soulillou^*,1,2

^* INSERM, UMR 643, CHU Nantes, Institut de Transplantation et de Recherche en Transplantation, ITERT, Université de Nantes, Faculté de Médecine, and CHU Hôtel Dieu, Nantes, France;
Service de Neurologie, Hôpital Laennec, CHU de Nantes, Nantes, France;
Weill Cornell Medical College, Division of Hematology-Oncology, New York, New York, USA;
Faculty of Science Walton Hall, Milton Keynes, United Kingdom; and
^|| Institut Cochin, Université Paris Descartes, INSERM, U567, and CNRS, UMR 8104, Paris, France

2. Correspondence: INSERM, UMR 643, Institut de Transplantation et de Recherches en Transplantation, ITERT, 30 Boulevard Jean Monnet, Nantes, 44900 France. E-mail: jean-paul.soulillou{at}univ-nantes.fr

ABSTRACT

Mechanisms of T lymphocyte trafficking in the brain remain unclear in MS. We hypothesized that MS is associated with increased CD4+ and CD8+ T lymphocyte trafficking across the BBB. To test this hypothesis, we calculated the frequency of PSGL-1+/CD4+ and PSGL-1+CD8+ or LFA-1+/CD4+/CD8+ T cells in the PBMC of 27 patients with a RR-MS (21 untreated and six IFN-β-treated) and 18 HI. Next, we measured their ex vivo TR across resting and TNF--activated human BBB-derived hCMEC/D3 endothelial layers under static conditions. The frequency of PSGL-1+CD4+ T lymphocytes was significantly higher in treated or untreated MS patients than HI. Furthermore, resting hCMEC/D3 TR of CD4+ lymphocytes (purified or in PBMC) from treated or untreated MS patients were significantly higher than those of HI and associated with significant enrichments of CD4+PSGL+ or CD4+PSGL-1+CD45RO+ T cells in their transmigrating fractions. The TR of CD4+ and CD8+ from MS patients across TNF--activated hCMEC/D3 were also significantly higher than that observed in HI. Resting hCMEC/D3 transmigration was blocked significantly by anti-PSGL-1/anti-LFA-1 in all groups, and anti-VLA-4 inhibited transmigration of MS T cells specifically. Purified PSGL-1-negative CD4+ lymphocytes transmigrated resting hCMEC/D3 with <10% of transmigrating cells re-expressing PSGL-1, suggesting PSGL-1-independent transmigration mechanisms. The frequency of PSGL-1 was unchanged in CD8+ cells from MS patients, whereas CD8+LFA-1^high were reduced significantly in IFN-β-treated patients specifically. Collectively, MS is associated with an expanding pool of PSGL-1+CD4+ T lymphocytes able to transmigrate the BBB endothelium in vitro and possibly contributing to brain pathology.

Key Words: LFA-1 • VLA-4 • p-selectin • VCAM-1 • ICAM-1 • inflammation • endothelium

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Editorial: PSGL-1—the hidden player in T cell trafficking into the brain in multiple sclerosis?

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				B. Engelhardt Editorial: PSGL-1--the hidden player in T cell trafficking into the brain in multiple sclerosis? J. Leukoc. Biol., November 1, 2009; 86(5): 1023 - 1025. [Full Text] [PDF]