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

Abstract

ABSTRACTJoint 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,CRTAMcorrelated 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 fromIl27ra-/-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-/-, andIl27ra-/-mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19+cells. Considering theex vivoregulation 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.