XCR1⁺ Conventional Type 1 Dendritic Cells Exacerbate the Inflammation in Osteogenic Arthritis Through IL-17A⁺CD8⁺ T Cells.

Abstract

Ankylosing spondylitis (AS) and enthesitis-related arthritis (ERA) are autoimmune bone diseases characterized by prominent heterotopic ossification and both have poor prognoses. The pathologic mechanisms of these diseases remain poorly understood. After single-cell RNA-sequencing and T cell receptor (TCR) profiling, we used flow cytometry and multiplex immunofluorescence to quantify and map specific immune-cell subsets within lesions of early rheumatoid arthritis and AS, analyzing a total of 33 patient specimens. Furthermore, we identified a peptide from versican, a chondroitin sulfate proteoglycan of ligament, to establish an AS mouse model. In the novel model, immune-cell quantification, spatial mapping, and targeted therapies were applied to elucidate the pathogenic roles of key cellular subpopulations. Conventional Type 1 dendritic cells (cDC1s) were enriched in the joints of patients with ERA and exhibited a high level of major histocompatibility complex (MHC) I antigen presentation, which robustly interact with CD8⁺ T cells. Moreover, cDC1s, harboring the molecular of MHC I antigen presentation, were detected in spinal ligament tissue of patients with AS. In mice, versican-derived peptide combined with Type II collagen stably and efficiently elicits a model exhibiting hallmark enthesitis and heterotopic ossification. In this model, cDC1s and IL-17A⁺CD8⁺ T cells were highly enriched in the ligamentous synovial tissues. Blocking the recruitment of cDC1s through XCL1-neutralizing antibody alleviates arthritis symptoms in vivo. Thus, cDC1s promote autoimmune reactions and osteoarticular lesions through IL-17A⁺CD8⁺ T cells. Targeting cDC1 represents a novel therapeutic target for bone remodeling arthritis.