Background/Purpose: Genetic and functional studies strongly support the role of T-cells in PsA pathophysiology. Effective targeting of T-cells requires a detailed understanding of their phenotypic and functional characteristics at the site of inflammation. This study aims to understand the different components of T-cell responses in the PsA synovium compared to the peripheral blood and investigate the effects of targeting broader pro-inflammatory signalling pathways by interfering with phosphodiesterase 4 (PDE4).

Methods: PsA Synovial tissue cell suspensions, matched synovial fluid mononuclear cells (SFMC) and PsA peripheral blood mononuclear cells (PBMC) were stimulated with PMA and ionomycin in the presence of Brefeldin A and analysed for CD4, CD8, CD161, IL-17A, IFNγ, GM-CSF and TNFα expression by flow cytometry. PsA synovial cell suspensions were cultured in the presence of PDE4 inhibitor, Rolipram (10μM) for 8hr followed by analysis of intracellular cytokines. Polyfunctional cytokine expression was determined by SPICE analysis. The effect of Rolipram treatment on the spontaneous secretion of IL-6, IL-8, MCP-1, IL-1β, RANTES, MMP-1 and MMP-3 was quantified by ELISA. Explants were also embedded in matrigel over a time-course of 1-21 days and synovial outgrowths assessed.

Results: PsA synovial infiltrating T-cells had increased frequencies of CD4 T helper subsets; Th1 (p<0.05), Th17 and exTh17 (p<0.05) compared to the peripheral blood. The production of GM-CSF, IL-17A and IFNγ, but not TNFα, was also higher in the synovial tissue compared to peripheral blood (p<0.05). Strikingly, polyfunctional cells co-expressing GM-CSF, TNF, IL17A and/or IFN-γ were significantly increased in the CD4, CD8, Th1, Th17 and exTh17 compartment of synovial T-cells. Analysis of disease activity revealed that polyfuncitonal cytokine expressing T-cells (p<0.01, r=0.89) and not monofunctional synovial T-cells (p=0.267, r=-0.05) are important to disease progression. Moreover, we revealed that PDE4 blockade can suppress the frequencies of these polyfunctional GM-CSF⁺TNFα⁺IL-17A⁺ and/or IFN-γ⁺ in CD8, CD4, Th1, Th17 and exTh17 cells (all p<0.05). Finally, using whole tissue synovial explants, which closely reflect the in-vivo inflamed microenvironment of the joint, we demonstrate that PDE4 blockade also inhibits the secretion of pro-inflammatory mediators and synovial invasiveness (p<0.05).

Conclusion: Immunophenotypic analysis of the synovial tissue of PsA patients shows accumulation of Th1, Th17 and exTh17 cells, with a specific increase in polyfunctional cells co-expressing GM-CSF⁺TNFα⁺IL-17A⁺ and/or IFN-γ⁺, exerting pleiotropic effects and disease progression. Neutralisation of these polyfunctional T-cells and synovial invasiveness by PDE4 may therefore produce optimal inhibition of pro-inflammatory signalling responses in the PsA synovium.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/polyfunctional-synovial-t-cell-responses-and-synovial-invasiveness-repressed-by-blockade-of-phosphodiesterase-4/