Positive feedback between cDC1s and CD8+ T cells typifies the inflammation of HLA-B27+ arthritis

Enthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis (JIA) with enthesitis and sacroiliitis, which differ from other types of JIA in symptoms, pathogenesis, and outcome. Although the association of human leukocyte antigen-B27 (HLA-B27) with ERA has been confirmed for decades, the pathogenesis of ERA is poorly understood. Here, we performed single-cell RNA-seq of 1,73,134 mononuclear cells extricated from patients with oligoarthritis (OligoA) or ERA and integrated 58,725 PBMCs of healthy people to profile the immune characteristic that discriminates ERA from OligoA. We found that conventional type 1 dendritic cells (cDC1s) were enriched in the joints of patients with ERA and exhibited a high level of MHC class I antigen presentation. Central memory CD8+ T cells critically contributed to the elevation of XCL1, recruiting XCR1+ cDC1 in joints of ERA. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) analyses confirmed an increased proportion and interaction of cDC1s and CD8+ T cells. In addition, macrophages occupied the causal position in the pathogenesis of OligoA, along with high expression of MHC class II molecules on macrophages and cDC2s in the joints. This study suggests that the positive feedback between cDC1s and CD8+ T cells is a key mediator of HLA-B27-positive arthritis pathogenesis.