title: Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1.
abstract: The 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.
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
authors.forename: D
authors.identifier: 0000-0001-6450-4521
authors.initials: D
authors.lastname: Bommarito
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hall
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
authors.forename: L S
authors.initials: LS
authors.lastname: Taams
authors.affiliation: Centre for Inflammation Biology and Cancer Immunology, Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
authors.forename: V M
authors.initials: VM
authors.lastname: Corrigall
mesh_terms: D000328:Adult; D000368:Aged; D015535:Arthritis, Psoriatic / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008131:London; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D013582:Synovial Fluid / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor
keywords: IL-6; PD-1; PD-L1; TNFα; inflammatory arthritis