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.
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-beta-treated) and 18 HI. Next, we measured their ex vivo TR across resting and TNF-alpha-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-alpha-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-beta-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.
Bahbouhi
Bouchaib
B
INSERM, UMR 643, Institut de Transplantation et de Recherches en Transplantation, ITERT, Nantes 44900, France.
Berthelot
Laureline
L
Pettré
Ségolène
S
Michel
Laure
L
Wiertlewski
Sandrine
S
Weksler
Babette
B
Romero
Ignacio-Andres
IA
Miller
Florence
F
Couraud
Pierre-Olivier
PO
Brouard
Sophie
S
Laplaud
David-Axel
DA
Soulillou
Jean-Paul
JP
D000328:Adult; D001812:Blood-Brain Barrier / Q000276:immunology*; D001921:Brain / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D016899:Interferon-beta / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D016899:Interferon-beta