Poster Presentation Multi-Omics Conference 2024

Proinflammatory impact of putative viral-specific CD8+ T cells infiltrating new-onset seropositive rheumatoid arthritis synovium (#133)

Hanno Nel 1 2 , Pascale Wehr 1 2 , Chenhao Zhou 1 2 , Christopher E Andoniou 3 4 , Iona S Schuster 3 5 , Joseph Yunis 1 2 6 , Stephanie Gras 7 8 , Helen M McGuire 9 , Helen Weedon 10 , Annabelle Small 11 , Katie Lowe 11 , John Saxon 12 , Benjamin Cai 1 2 , James Rae 13 , Robert G Parton 13 14 , Helen E Farrell 15 , Ahmed M Medhi 1 6 , Zewen K Tuong 1 12 , Raymond Steptoe 1 2 , Mariapia A Degli-Esposti 3 5 , Di Yu 1 2 12 , Mihir D Wechalekar 10 11 , Ranjeny Thomas 1 2
  1. University of Queensland, Woolloongabba, QLD, Australia
  2. Faculty of Medicine, UQ, Frazer Institute, Brisbane, Qld, Australia
  3. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash, Victoria, Australia
  4. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
  5. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
  6. Facility for Advanced Bioinformatics, Queensland Cyber Infrastructure Foundation Ltd,, Brisbane, Qld, Australia
  7. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Melbourne, Victoria, Australia
  8. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  9. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Charles Perkins Centre, Camperdown, New South Wales, Australia
  10. Rheumatology Department, Flinders Medical Centre, Bedford Park, South Australia, Australia
  11. Flinders University, College of Medicine & Public Health, Bedford Park, South Australia, Australia
  12. Ian Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, Brisbane, Qld, Australia
  13. Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia
  14. School of Chemistry and Molecular Biosciences and Centre for Children's Health Research, The University of Queensland, St. Lucia, Qld, Australia
  15. Centre for Microscopy and Microanalysis, The University of Queensland, St. Lucia, Qld, Australia

Rheumatoid Arthritis (RA) is primarily considered to be an MHC class II-associated autoimmune disease where effector CD4+ T cell play a role in disease pathogenesis. Infiltrating T cells with expanded T cell receptor (TCR)-β clonotypes, some of which are viral-antigen-reactive, have been identified in synovial tissue (ST) of RA patients. Recently, single cell sequencing technologies have also identified large numbers of CD8+ cytotoxic T lymphocytes (CTL) expressing granzyme B and/or granzyme K infiltrating ST in active, established RA. We used multi-omic tools, including single cell RNA and TCR sequencing and Imaging Mass cytometry, to assess the differential ST cellular landscape and address the contribution of virus-specific CD8+ T cells to the development of inflammatory arthritis.  We studied paired peripheral blood and ST of ten drug-naïve patients with recent-onset untreated seropositive RA. ST had either predominant diffuse-myeloid (DM, n=4) or lymphoid (L, n=6) histological pathology.  We found CD4-like T, B and myeloid cell transcriptomic features of DM and L ST were distinct. While CD4-like regulatory and CD8+ effector-memory T-cell (TEM), including granzyme B/K clonotypes generally infiltrated ST, cytotoxic CD4-like peripheral helper TCR clonotypes and flare-associated monocytes were enriched in L ST. Remission-associated macrophages were enriched in DM ST. A proportion of CD8+ TCRs in ST mapped to viral epitopes at the HLA-class I-restricted TCR-β level. To evaluate the impact of viral infection or viral-induced CTLs, we modelled antigen-induced arthritis (AIA) in mice with latent murine cytomegalovirus or mice recovered from acute lympho-choriomeningitis virus. AIA was more severe after cleared acute or latent infection, due to viral-induced antigen-specific CD8+ T-cell cross-activation of arthritogenic CD4+ T cells. Thus, putative viral-specific CD8+ TEM have the potential to cross-activate antigen-specific CD4+ T-cell function to perpetuate ST inflammation in RA.