T cell exhaustion: next-generation target of autoimmune diseases?

Exhausted T cells (Tex), characterized by impaired cytotoxic function, play a detrimental role in anti-tumor and anti-infection immunity but represent promising therapeutic targets for autoimmune diseases. Persistent exposure to auto-antigens drives autoreactive CD8+ or CD4+T cells toward an exhausted-state, thereby mitigating excessive damage to healthy tissues. Inducing T cell exhaustion may offer a targeted approach to suppress pathological autoimmunity. In this review, we describe the markers, characteristics, and developmental phases of T cell exhaustion, discuss its close association with autoimmune diseases, and highlight Tex as a potential biomarker. We also summarize Tex-targeted therapeutic strategies, including inhibitory receptor activation, TCR overstimulation, and metabolic intervention, to provide insights for future treatments. The clinical translation gap of Tex-targeted therapy has also been proposed from stability, safety, and disease-specific considerations. Although challenges remain in areas such as antigen specificity and tenuous tolerance, therapies targeting Tex hold considerable potential to disrupt pathogenic circuits, realize disease remission, and reduce the risk of relapse in autoimmune diseases.