Interleukin-17A Is Produced by CD4+ but Not CD8+ T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis.

Abstract

ObjectiveInterleukin‐17A (IL‐17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells in PsA have been recognized via flow cytometry as a source of IL‐17A production, it is not clear whether CD8+ T cells secrete IL‐17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL‐17A and TNF in the synovial fluid (SF) from patients with PsA and investigate the impact of CD8+ T cells on IL‐17A production.Methods IL‐17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment‐naive patients with PsA, and blood samples from 22 healthy donors. IL‐17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti‐CD3/anti‐CD28 or phorbol myristate acetate (PMA) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast‐like synoviocytes (FLS) (n = 5–6). To evaluate the differential allogeneic effects of neutralizing IL‐17A and TNF, SF CD4+ T cells and PsA FLS cocultures were also used (n = 5–6).ResultsFlow cytometry analyses of SF samples from patients with PsA showed IL‐17A positivity for CD4+ and CD8+ T cells (IL‐17A, median 0.71% [interquartile range 0.35–1.50%] in CD4+ cells; median 0.44% [interquartile range 0.17–1.86%] in CD8+ T cells).However, only CD4+ T cells secreted IL‐17A after anti‐CD3/anti‐CD28 activation, when cultured alone and in cocultures with PsA monocytes or PsA FLS (each P < 0.05). Remarkably, CD8+ T cells only secreted IL‐17A after 4‐ or 72‐hour stimulation with PMA/ionomycin. Anti–IL‐17A and anti‐TNF treatments both inhibited PsA synovitis ex vivo. Neutralizing IL‐17A strongly inhibited IL‐6 (P < 0.05) and IL‐1β (P < 0.01), while anti‐TNF treatment was more potent in reducing matrix metalloproteinase 3 (MMP‐3) (P < 0.05) and MMP‐13.Conclusion CD8+ T cells, in contrast to CD4+ T cells, in SF specimens obtained from PsA patients did not secrete IL‐17A following T cell receptor activation. Overlapping, but distinct, effects at the level of inflammatory cytokines and MMPs were found after neutralizing IL‐17A or TNF ex vivo in a human model of PsA synovitis.