Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1.

Abstract

SummaryThe programmed cell death 1 (PD‐1) receptor plays a major role in regulating T cell activation. Our aim was to determine how inflammation influences PD‐1‐mediated T cell suppression. Flow cytometry analysis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovial fluid (SF) mononuclear cells showed an increase in the percentage of PD‐1+ cells within the CD4+ and CD8+ T cell compartment compared to paired peripheral blood (PB). Upon in‐vitro T cell receptor (TCR) stimulation of healthy control (HC) CD4+ T cells in the presence of plate‐bound PD‐L1fc chimera, significantly decreased proliferation and interferon (IFN)‐γ secretion was observed. In contrast, CD4+ T cells from RA and PsA PB and SF appeared resistant to such PD‐1‐mediated inhibition. Addition of the proinflammatory cytokines tumour necrosis factor (TNF)α, interleukin (IL)‐6 and IL‐1β, which were increased in RA and PsA SF compared to osteoarthritis (OA) SF, consistently abrogated PD‐1‐mediated suppression in HC CD4+ T cell cultures. This effect was reversed by inhibitors of these cytokines. Soluble PD‐1 (sPD‐1) levels were increased in cell culture supernatants from TNFα and IL‐6‐stimulated cultures compared to untreated controls, and also in RA and PsA, but not in OA, serum and SF. Functionally, addition of sPD‐1fc counteracted PD‐1‐mediated suppression of HC CD4+ T cells, and increased T cell proliferation in HC CD4+ T cell/monocyte co‐cultures. These in‐vitro findings indicate that CD4+ T cells from patients with RA and PsA show increased resistance to PD‐1‐mediated suppression, which may be explained in part by the presence of soluble PD‐1 in the inflammatory environment.