Article Text

Download PDFPDF
Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis
  1. Achilleas Floudas1,
  2. Nuno Neto2,2,
  3. Carl Orr3,
  4. Mary Canavan1,
  5. Phil Gallagher4,
  6. Conor Hurson4,
  7. Michael G Monaghan2,
  8. Sunil Nagpar5,
  9. Ronan H Mullan6,
  10. Douglas J Veale3,
  11. Ursula Fearon1
  1. 1Department of Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
  2. 2Department of Mechanical and Manufacturing Engineering, Trinity College Dublin, Dublin, Ireland
  3. 3Department of Rheumatology, EULAR Centre of excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent’s University Hospital, UCD, Dublin, Ireland
  4. 4Department of Orthopaedics, St Vincent’s University Hospital, Dublin, Ireland
  5. 5Department of Immunology, Janssen Research & Development, Immunology, Philadelphia, Pennsylvania, USA
  6. 6Department of Rheumatology, Tallaght University Hospital, Dublin, Dublin, Ireland
  1. Correspondence to Professor Ursula Fearon, Department of Molecular Rheumatology, Trinity College Dublin, Dublin, Ireland; Fearonu{at}tcd.ie

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+ CD8dim T-cells in IAR and RA but not HC synovial tissue. CD4+ CD8dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4+ CD8dim 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.

  • T-lymphocyte subsets
  • arthritis
  • rheumatoid
  • autoimmune diseases

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. RNAseq data are available in a public, open access repository (NCBI’s Gene Expression Omnibus database (accession number GSE154988)). Data are available upon reasonable request

Statistics from Altmetric.com

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. RNAseq data are available in a public, open access repository (NCBI’s Gene Expression Omnibus database (accession number GSE154988)). Data are available upon reasonable request

View Full Text

Footnotes

  • Handling editor Josef S Smolen

  • Twitter @mary_canavan, @drmgmonaghan

  • Contributors Contributorship conceptualisation: AF, UF and DJV; methodology: AF, NN; software: AF; validation: AF, NN; formal analysis: AF, UF, DJV, SN; investigation: AF, UF, DJV; resources: UF, DJV, data curation: AF, UF, DJV, CO, RHM, MC, PG, CH; writing—original draft preparation: AF, UF, DJV, NN, MGM; writing—review and editing, AF, UF, DJV; visualisation, AF, UF, DJV; supervision: UF, DJV; project administration: UF, DJV; funding acquisition: UF, DJV.

  • Funding This research was funded by Health Research Board of Ireland, grant number ILP-POR-2017-047, Centre for Arthritis and Rheumatic Diseases, CARD-2019-01, and Arthritis Ireland.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.