CD8⁺T cell exhaustion: the potential for treating autoimmune diseases

Exhausted CD8⁺T cells (CD8⁺Tex), characterized by progressive dysfunction and sustained inhibitory receptor expression, emerge as a potential therapeutic target for autoimmune diseases. While Tex impairs antitumor immunity, the reduced autoreactivity prevents the functioning of pathogenic CD8⁺T cells, contrasting with broad immunosuppression from conventional therapies. This review oveviews Tex drivers - inhibitory receptor upregulation, metabolic reprogramming, cytokine signaling, and regulatory immune cells crosstalk. We also distinguished Tex from anergy and senescence, emphasizing its superiority in inducibility and reduced risks in autoimmune disease treatment. Therapeutic strategies to promote Tex, such as immune checkpoint agonists, TCR overactivation, metabolic modulation, mechanical stress, and regulatory cell engagement, are critically evaluated. Challenges include ensuring specificity, timing interventions preempting pathogenic T cell activation, and leveraging various advancements in drug delivery. By reframing exhaustion as a protective mechanism, this approach aims to shift treatment paradigms from symptom management to pathogenic circuit disruption, offering a roadmap for next-generation precision immunotherapies for autoimmune diseases.