title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Amalia P
authors.initials: AP
authors.lastname: Raptopoulou
authors.forename: George
authors.initials: G
authors.lastname: Bertsias
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Makrygiannakis
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Verginis
authors.forename: Iraklis
authors.initials: I
authors.lastname: Kritikos
authors.forename: Maria
authors.initials: M
authors.lastname: Tzardi
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
authors.forename: Prodromos
authors.initials: P
authors.lastname: Sidiropoulos
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
mesh_terms: D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000172:deficiency / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins; D007371:Interferon-gamma