Pathogenicity of functionally activated PD-1⁺CD8⁺ cells and counterattacks by muscular PD-L1 through IFNγ in myositis

Programmed-cell-death 1 (PD-1) expression is associated not only with T-cell activation but with exhaustion. Specifically, PD-1⁺ T cells present an exhausted phenotype in conditions of chronic antigen exposure, such as tumor microenvironments and chronic viral infection. However, the immune status regarding exhaustion of PD-1⁺CD8⁺ T cells in chronic autoimmune diseases including idiopathic inflammatory myopathies (IIMs) remains unclear. We aimed to clarify the role of PD-1⁺CD8⁺ T cells and PD-1 ligand (PD-L1) in IIMs. We showed that PD-1⁺ cells infiltrated into PD-L1-expressing muscles in patients with IIMs and immune checkpoint inhibitor-related myopathy. According to the peripheral blood immunophenotyping, the PD-1⁺CD8⁺ cell proportions were comparable between the active and inactive patients. Of note, PD-1⁺CD8⁺ cells in the active patients highly expressed cytolytic molecules, indicating their activation, while PD-1^-CD8⁺ cells expressed low levels of cytolytic molecules in the active and inactive patients. A part of PD-1⁺CD8⁺ cells expressed the HMG-box transcription factor TOX highly and presented the exhausted phenotype in the active patients. Among PD-1⁺CD4⁺ T cells, PD-1^highCXCR5^-CD45RO⁺CD4⁺ peripheral helper T cells were increased in the active patients. PD-L1-deficient mice developed severer C-protein-induced myositis (CIM), a model of polymyositis, with abundant infiltration of PD-1⁺CD8⁺ cells expressing cytolytic molecules than wild-type mice, indicating pathogenicity of the PD-1⁺CD8⁺ cells and the protective role of PD-L1. The deficiency of IFNγ, a general PD-L1-inducer, impaired muscular PD-L1 expression and exacerbated CIM, indicating IFNγ-dependent muscular PD-L1 regulation. IFNγ-induced PD-L1 on myotubes was protective in an established muscle injury model. In conclusion, PD-1⁺CD8⁺ T cells rather than PD-1^-CD8⁺ T cells were a pathogenic subset of IIMs. Muscular PD-L1 was regulated by IFNγ and exerted protective properties in IIMs.