IL-6 and IL-27 negatively regulate CRTAM-expressing CD4+T-cells associated with lymphoid-driven synovitis

ABSTRACT– Joint pathology in rheumatoid arthritis is heterogeneous, with histology providing evidence of fibroblast-driven, myeloid-driven, and lymphoid-driven synovitis. However, the immuno-modulatory pathways underlying their development remain unclear. Profiling synovial tissues from rheumatoid arthritis patients and mice with antigen-induced arthritis, we identified a subset of synovial infiltrating CD4 + T-cells expressing CRTAM (class-I MHC-restricted T-cell-associated molecule). In human synovial biopsies, CRTAM correlated with the expression of effector cytokines ( IL21 , IFNG ), chemokine receptors ( CXCR3 , CXCR4 , CCR5 ), granzymes ( GZMA , GZMB , GZMK ), and regulatory factors ( TIGIT , EOMES , BATF ) linked with T-cell-mediated immunity. Studies of antigen-induced arthritis showed that CRTAM + CD4 + T-cells accumulate in the inflamed synovium following disease onset. CRTAM + CD4 + T-cells were particularly abundant in synovial tissue from Il27ra -/- mice displaying ectopic lymphoid-like structures. CADM1 (cell adhesion molecule-1), the endogenous ligand for CRTAM, was also expressed in human synovitis and synovial tissues from wild-type, Il6ra -/- , and Il27ra -/- mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19 + cells. Considering the ex vivo regulation of CRTAM, we identified that activation of naïve CD4 + T-cell increased CRTAM expression. This induction was blocked by IL-6 and IL-27, with further studies identifying a role for STAT3 in controlling the CRTAM transcriptional repressor, ZEB1. These results provide insights into the cytokine control of CRTAM on CD4 + T-cells and support the involvement of CRTAM + CD4 + T-cells in lymphoid-driven synovitis.