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: D Bommarito, C Hall, L S Taams, V M Corrigall
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 188 Issue 3 Pg. 455-466 (06 2017) ISSN: 1365-2249 [Electronic] England
• PMID: 28245522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

Chemical References

• Cytokines
• Programmed Cell Death 1 Receptor

Topics

• Adult
• Aged
• Arthritis, Psoriatic (immunology)
• Arthritis, Rheumatoid (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Case-Control Studies
• Coculture Techniques
• Cytokines (metabolism)
• Female
• Flow Cytometry
• Humans
• London
• Lymphocyte Activation
• Male
• Middle Aged
• Osteoarthritis (immunology)
• Programmed Cell Death 1 Receptor (metabolism)
• Synovial Fluid (immunology)
• Up-Regulation