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 Rheum. 2010 Jul;62(7):1870-80. doi: 10.1002/art.27500.


Objective: 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.

Methods: 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.

Results: 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-gamma (IFNgamma) 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 (IFNgamma and interleukin-17) in response to type II collagen. PDL-1.Fc treatment ameliorated the severity of CIA and reduced T cell responses.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Surface / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • B7-1 Antigen / metabolism
  • B7-H1 Antigen
  • Female
  • Flow Cytometry
  • Humans
  • Interferon-gamma / metabolism
  • Lymphocyte Activation
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Peptides / deficiency
  • Peptides / metabolism
  • Programmed Cell Death 1 Receptor
  • Recombinant Proteins / pharmacology
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Up-Regulation


  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Membrane Glycoproteins
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Recombinant Proteins
  • Interferon-gamma