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

TY - JOUR

T1 - Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1

AU - Bommarito, D

AU - Hall, C

AU - Taams, L S

AU - Corrigall, V M

N1 - © 2017 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

PY - 2017/4/3

Y1 - 2017/4/3

N2 - 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.

AB - 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.

U2 - 10.1111/cei.12949

DO - 10.1111/cei.12949

M3 - Article

C2 - 28245522

SN - 0009-9104

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

ER -