Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Proinflammatory impact of viral-specific CD8+ T cells infiltrating new-onset seropositive rheumatoid arthritis synovium (#125)

Pascale Wehr 1 , Hanno Nel 1 , Chris E Andoniou 2 , Iona Schuster 2 , Joseph Yunis 1 , Stephanie Gras 3 , Helen McGuire 4 , Helen Weedon 5 , Annabelle Small 6 , Katie Williams 5 , Chen BB Chai 1 , James Rae 1 , Robert Parton 1 , Helen Farrell 1 , Ahmed Mehdi 1 , Raymond Steptoe 1 , Mariapia Degli-Esposti 2 , Di Yu 1 , Mihir Wechalekar 5 , Ranjeny Thomas 1
  1. University of Queensland, Woolloongabba, QLD, Australia
  2. Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash, Victoria, Australia
  3. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Melbourne, Victoria, Australia
  4. Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
  5. Rheumatology Department, Flinders Medical Centre, Bedford Park, South Australia, Australia
  6. Flinders University, College of Medicine & Public Health, Bedford Park, South Australia, Australia

Anti-citrullinated protein autoantibody (ACPA)+ rheumatoid arthritis (RA) is associated with specific HLA-DR genotypes, ectopic lymphoid follicles producing ACPA in synovial tissue (ST) and synovial expansion of CD4+ effector-memory, including peripheral helper, T cells. Some clonally expanded ST CD4+ T cells in early RA respond to viral antigens. CD8+granzyme-K+ cytotoxic T lymphocytes (CTL) also infiltrate ST in established RA, while lymph node-resident CD8+ T cells in seropositive at-risk individuals or RA are enriched in CD45RO, CD69 and CXCR5. To address the ST TCR repertoire in ACPA+ HLA-DRB1*04:01+ DMARD-naive early RA, we assessed T cell clonotypes and their location in ST. A large proportion of clonally-expanded T cells in peripheral blood (PB) and ST had signatures of polyfunctional CD4+ or CD8+ CTL expressing TNF, IFNG, GZMK, GZMA and GZMB. A smaller number of CD4+ T cell clonotypes unique to ST had Th2-like (expressing GATA3) and central memory-like transcriptomic profiles, with evidence of IL-6-signaling (expressing CCR7, ICOS, IL6ST). In-silico prediction of CMV epitope recognition by clonally-expanded CD8+ TCR sequences was confirmed with a CMV-specific tetramer. Perivascular clonotypic GZMB+CD8+ T cells were co-located with CD4+ T cells, dendritic cells (DCs) and Thy1+ fibroblasts. In a mouse model of latent mCMV, antigen-induced arthritis (AIA) was more severe, with increases in IFN-γ and TNF production by OVA-specific and mCMV-specific lymph-node T cells, than uninfected OVA-AIA mice. These data suggest that positive feedback from viral-specific T cells may enhance arthritogenic antigen presentation by DCs, and reciprocal enhanced CD4+ T-cell help for CTL and autoantibodies. This hypothesis would advocate strongly for the use of antigen-specific tolerising therapies in regulating bystander responses to promote the control of inflammation in RA.