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

Abstract New-onset HLA-DR-associated anti-citrullinated protein autoantibody (ACPA) + rheumatoid arthritis (RA) synovial tissue (ST) contains highly-expanded TCR-αβ clonotypes, some viral-antigen-reactive. However, it is unknown how viral-specific T-cells sustain ACPA + RA. We studied paired peripheral blood (PB) and ST TCR repertoires in drug-naïve ACPA + HLA-DRB1*04:01 + diffuse-myeloid RA ST pathology. To model effects of viral infection, we induced ovalbumin antigen-induced arthritis (AIA) in mice with latent murine-cytomegalovirus or recovered from acute lymphocytic-choriomeningitis virus. We show that most clonally-expanded CD8 + T cells had polyfunctional TNF + IFNγ + cytotoxic T-lymphocyte (CTL) signatures. Transcriptomic profiles of ST CD4 + T-cell clonotypes were Th2-like and IL-6-signaled central memory-like. CMV-specific tetramers confirmed in-silico prediction of viral-epitope recognition by CTL. Perivascular GZMB + CD8 + T cells co-localized with CD4 + T-cells, dendritic cells, fibroblasts and IL-6. After viral infection, AIA severity increased with enhanced viral and ovalbumin-specific TNF + IFN-γ + T-cell cytokines, suggesting that in the diffuse-myeloid rheumatoid-synovial perivascular niche, polyfunctional bystander-CTL reinforce myeloid- and CD4 + T-cell activation.