Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis. Issue 2 (1st October 2021)

• Record Type: Journal Article
• Authors: Floudas, Achilleas; Neto, Nuno; Orr, Carl; Canavan, Mary; Gallagher, Phil; Hurson, Conor; Monaghan, Michael G; Nagpar, Sunil; Mullan, Ronan H; Veale, Douglas J; Fearon, Ursula
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 2(2022)
• Page Start: 193
• Page End: 205
• Publication Date: 2021-10-01
• Subjects: T-lymphocyte subsets -- arthritis -- rheumatoid -- autoimmune diseases; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2021-220458
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: This study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation. Methods: Pathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering. Flow-imaging was utilised to confirm specific T-cell cluster identification. Fluorescent lifetime imaging microscopy (FLIM) was used to visualise metabolic status of sorted T-cell populations. Results: Increased plasticity of Tfh cells and CD4 T-cell polyfunctionality with enriched memory Treg cell responses was demonstrated in RA patient synovial tissue. Synovial-tissue RNAseq analysis reveals that enrichment in T-cell activation and differentiation pathways pre-dates the onset of RA. Switch from potentially protective IL-4 and granulocyte macrophage colony stimulating factor (GMCSF) dominated polyfunctional CD4 T-cell responses towards pathogenic polyfunctionality is evident in patient with IAR and RA synovial tissue. Cluster analysis reveals the accumulation of highly polyfunctional CD4 + CD8 dim T-cells in IAR and RA but not HC synovial tissue. CD4 + CD8 dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4 + CD8 dim T-cells correlates with RA disease activity. Conclusion: Switch from potentially protective to pathogenic T-cell polyfunctionality pre-dates the onset of clinical inflammation and constitutes an opportunity for therapeutic intervention in RA.