Drs. Raptopoulou and Bertsias contributed equally to this work.
The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis
Article first published online: 6 APR 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 7, pages 1870–1880, July 2010
How to Cite
Raptopoulou, A. P., Bertsias, G., Makrygiannakis, D., Verginis, P., Kritikos, I., Tzardi, M., Klareskog, L., Catrina, A. I., Sidiropoulos, P. and Boumpas, D. T. (2010), The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis & Rheumatism, 62: 1870–1880. doi: 10.1002/art.27500
- Issue published online: 29 JUN 2010
- Article first published online: 6 APR 2010
- Manuscript Accepted: 30 MAR 2010
- Manuscript Received: 6 MAY 2009
- Hellenic Society of Rheumatology
- Pancretan Health Association
- Hellenic Ministry of Education
- Hellenic Republic
- European Union (EPEAEK Fund and Sixth Framework Programme AutoCure program)
T cells play a major role in the pathogenesis of rheumatoid arthritis (RA). The programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway is involved in peripheral tolerance through inhibition of T cells at the level of synovial tissue. The aim of this study was to examine the role of PD-1/PDL-1 in the regulation of human and murine RA.
In synovial tissue and synovial fluid (SF) mononuclear cells from patients with RA, expression of PD-1/PDL-1 was examined by immunohistochemistry and flow cytometry, while PD-1 function was assessed in RA peripheral blood (PB) T cells after stimulation of the cells with anti-CD3 and PDL-1.Fc to crosslink PD-1. Collagen-induced arthritis (CIA) was induced in PD-1−/− C57BL/6 mice, and recombinant PDL-1.Fc was injected intraperitoneally to activate PD-1 in vivo.
RA synovium and RA SF were enriched with PD-1+ T cells (mean ± SEM 24 ± 5% versus 4 ± 1% in osteoarthritis samples; P = 0.003) and enriched with PDL-1+ monocyte/macrophages. PD-1 crosslinking inhibited both T cell proliferation and production of interferon-γ (IFNγ) in RA patients; PB T cells incubated with RA SF, as well as SF T cells from patients with active RA, exhibited reduced PD-1–mediated inhibition of T cell proliferation at suboptimal, but not optimal, concentrations of PDL-1.Fc. PD-1−/− mice demonstrated increased incidence of CIA (73% versus 36% in wild-type mice; P < 0.05) and greater severity of CIA (mean maximum arthritis score 5.0 versus 2.3 in wild-type mice; P = 0.040), and this was associated with enhanced T cell proliferation and increased production of cytokines (IFNγ and interleukin-17) in response to type II collagen. PDL-1.Fc treatment ameliorated the severity of CIA and reduced T cell responses.
The negative costimulatory PD-1/PDL-1 pathway regulates peripheral T cell responses in both human and murine RA. PD-1/PDL-1 in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA.