Characterization of pathogenic synovial IL-17A-producing CD8⁺ T cell subsets in collagen-induced arthritis

Using a murine collagen-induced arthritis model, we characterized the heterogeneity of synovial CD8⁺ T cells based on the expression of chemokine receptors, cytokines, and nuclear transcription factors. Four subsets, i.e. CXCR3^-CCR4^- cells, CXCR3⁺CCR4^- cells, CXCR3⁺CCR4⁺ cells, and CXCR3^-CCR4⁺ cells, were present in synovial CD8⁺CD62L^-CCR6⁺IL-23R⁺CCR10^- T cells. CXCR3^-CCR4^- cells belonged to exhausted CD8⁺ T cells. CXCR3⁺CCR4^- cells were Tc17.1 cells expressing both IL-17A and IFN-γ. CXCR3⁺CCR4⁺ cells were transitional Tc17.1 cells expressing IL-17A but lower IFN-γ, and CXCR3^-CCR4⁺ cells were Tc17 cells expressing IL-17A but no IFN-γ. Transitional Tc17.1 cells can differentiate into Tc17.1 cells in vitro under the instruction of IL-12. Tc17.1 cells and transitional Tc17.1 cells strongly induced the expression of pro-inflammatory mediators in synovial fibroblasts, whereas Tc17 cells were less potent in doing so. IFN-γ was involved in the higher pathogenicity of Tc17.1 cells and transitional Tc17.1 cells on synovial fibroblasts. This study expands the understanding of Tc17 biology by unveiling the phenotypic and functional heterogeneity of synovial IL-17A-expressing CD8⁺ T cells. These heterogeneous IL-17A-expressing CD8⁺ T cells could be novel therapeutic targets in future arthritis treatment.