Floudas A, Neto N, Orr C, et al. - The transition from potentially protective to pathogenic T-cell polyfunctionality precedes the onset of clinical inflammation and represents an opportunity for therapeutic intervention in rheumatoid arthritis (RA).

• Pathway enrichment analysis was performed on previously obtained RNAseq data from synovial biopsies from RA (n = 118), IAR (n = 20) and HC (n = 44).

• Tfh cell plasticity and CD4 T-cell polyfunctionality were found to be increased in RA patient synovial tissue, along with enriched memory Treg cell responses.

• T-cell activation and differentiation pathways are enriched in synovial-tissue RNAseq analysis, which predates the onset of RA.

• In patients with IAR and RA synovial tissue, there is a shift from potentially protective IL-4 and granulocyte macrophage colony stimulating factor dominated polyfunctional CD4 T-cell responses to pathogenic polyfunctionality.

• Cluster analysis shows that highly polyfunctional CD4+ CD8^dim T-cells accumulate in IAR and RA but not HC synovial tissue.

• CD4+ CD8^dim T-cells exhibit increased oxidative phosphorylation utilization, which is characteristic of metabolically primed memory T-cells.

• The frequency of synovial CD4+ CD8^dim T-cells is related to RA disease activity.