Polymyositis (PM) and dermatomyositis (DM), subsets of idiopathic inflammatory myopathies (IIMs), are chronic autoimmune diseases that primarily affect striated muscles [1]. Although glucocorticoids are used as a cornerstone of IIM treatment, they are associated with various adverse effects due to targeting various cell populations [2]. Concomitant use of immunosuppressive agents, such as methotrexate, azathioprine, and calcineurin inhibitors, is beneficial for the remission induction and reduction of cumulative glucocorticoid dose during the disease course [2]. However, some patients are refractory to these existing treatments. Therefore, the identification of the pathogenic cell populations could lead to the development of more effective therapies.

Programmed-cell-death 1 (PD-1) is expressed on primarily activated T cells [3]. When PD-1 interacts with its ligand, PD-L1, activated T cells receive inhibitory signals and lose their effector functions [4]. The PD-1/PD-L1 immune checkpoint might be involved in the pathogenesis of IIMs. Immune-related myopathy (irMyopathy) occasionally develops during PD-1/PD-L1 immune checkpoint inhibition therapy aimed at sustained activation of PD-1+ T cells in the treatment of malignancies [[5], [6], [7]]. Additionally, in the muscle tissues of patients with some IIM subsets, PD-L1 is expressed on the muscle fibers at local inflammatory sites with PD-1+ cell infiltration [8]. Based on these observations, it appears that the PD-1/PD-L1 immune checkpoint protects muscles from attacks by PD-1+ effector cells in IIMs. Actually, the protective role of PD-L1 in the target tissues has been reported in several autoimmune disease models, such as experimental autoimmune encephalomyelitis and insulin-dependent diabetes mellitus [[9], [10], [11], [12], [13], [14]].

IFNγ, produced from effector cells, including cytotoxic CD8+ T cells, has pro- and anti-inflammatory activities with the functional outcome dependent on the physiological and pathological conditions [15,16]. In particular, IFNγ is a major inducer of PD-L1 in various cell types, such as human antigen-presenting cells, vascular endothelial cells, and various tumor cells [[15], [16], [17], [18], [19], [20]]. PD-L1 induced by IFNγ could contribute to immune evasion and hampers antitumor immunity [15,16,21,22]. We previously demonstrated that IFNγ deficiency exacerbates C-protein-induced myositis (CIM), a murine model of cytotoxic CD8+ T cell-mediated myositis [23]. This result indicates that IFNγ is protective in CIM development. Considering the immunoinhibitory mechanisms by IFNγ, specifically PD-L1 regulation, this observation might be linked to the possible involvement of PD-L1 as a protective factor and PD-1+ cells as effector cells in the pathogenesis of CIM.

Thus, PD-1+ cells are assumed to be pathogenic in IIMs. However, these cells are also reported to be associated with an exhausted phenotype in conditions of chronic antigen exposure, such as tumor microenvironments and chronic viral infection [[24], [25], [26], [27], [28]]. The exhausted T cells in chronic conditions increase PD-1 expression and decrease the capacity for producing effector cytokines and cytolytic molecules such as perforin and granzyme B [[26], [27], [28]]. Recently, the HMG-box transcription factor TOX has been reported to be a central regulator inducing PD-1+CD8+ T cell exhaustion in chronic infections and cancers [29]. In the chronic virus infection model, TOXhighPD-1highCD8+ T cells express high levels of various exhaustion markers, including PD-1, CTLA4, TIM-3, and LAG-3, while TOX deficiency enhances the effector function of CD8+ T cells. Similar to chronic viral infection and tumor microenvironments, T cells at the inflammation sites in the target organs seem to be chronically exposed to autoantigens in autoimmune diseases, including IIMs. In other words, whether the PD-1+ cells are activated as effector cells or exhausted in IIMs remains unclear. In order to clarify the pathogenic role of PD-1+ cells and protective mechanisms of IFNγ in IIMs, we analyzed the immunophenotyping of PD-1+ cells focused on the expression of cytolytic molecules and TOX as well as the protective effects of PD-L1 induced by IFNγ in the muscles using samples from IIM patients and CIM mice.