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‐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. 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.