PMID- 32243724 OWN - NLM STAT- MEDLINE DCOM- 20201211 LR - 20210110 IS - 2326-5205 (Electronic) IS - 2326-5191 (Print) IS - 2326-5191 (Linking) VI - 72 IP - 8 DP - 2020 Aug TI - 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. PG - 1303-1313 LID - 10.1002/art.41271 [doi] AB - OBJECTIVE: Interleukin-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). RESULTS: Flow 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-1beta (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. CI - (c) 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. FAU - Xu, Xiaofei AU - Xu X AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Davelaar, Nadine AU - Davelaar N AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Mus, Anne-Marie AU - Mus AM AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Asmawidjaja, Patrick S AU - Asmawidjaja PS AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Hazes, Johanna M W AU - Hazes JMW AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Baeten, Dominique L P AU - Baeten DLP AD - Academic Medical Center, Amsterdam, The Netherlands. FAU - Vis, Marijn AU - Vis M AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Bisoendial, Radjesh J AU - Bisoendial RJ AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Prens, Errol P AU - Prens EP AD - Erasmus Medical Center, Rotterdam, The Netherlands. FAU - Lubberts, Erik AU - Lubberts E AUID- ORCID: 0000-0002-3566-040X AD - Erasmus Medical Center, Rotterdam, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200708 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (IL17A protein, human) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-17) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Tumor Necrosis Factor-alpha) RN - 56092-81-0 (Ionomycin) RN - NI40JAQ945 (Tetradecanoylphorbol Acetate) SB - IM MH - Adult MH - Arthritis, Psoriatic/drug therapy/immunology MH - CD4-Positive T-Lymphocytes/*drug effects/immunology MH - CD8-Positive T-Lymphocytes/*drug effects/immunology MH - Cell Culture Techniques MH - Female MH - Flow Cytometry MH - Humans MH - Inflammation Mediators/*metabolism MH - Interleukin-17/*biosynthesis MH - Ionomycin/pharmacology MH - Lymphocyte Activation/drug effects/immunology MH - Male MH - Receptors, Antigen, T-Cell/*administration & dosage/immunology MH - Synovial Fluid MH - Synoviocytes/drug effects/immunology MH - Synovitis/drug therapy/immunology MH - Tetradecanoylphorbol Acetate/pharmacology MH - Tumor Necrosis Factor-alpha/*metabolism PMC - PMC7497075 EDAT- 2020/04/04 06:00 MHDA- 2020/12/15 06:00 PMCR- 2020/09/17 CRDT- 2020/04/04 06:00 PHST- 2019/06/20 00:00 [received] PHST- 2020/03/24 00:00 [accepted] PHST- 2020/04/04 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/04/04 06:00 [entrez] PHST- 2020/09/17 00:00 [pmc-release] AID - ART41271 [pii] AID - 10.1002/art.41271 [doi] PST - ppublish SO - Arthritis Rheumatol. 2020 Aug;72(8):1303-1313. doi: 10.1002/art.41271. Epub 2020 Jul 8.