Cytokine-mediated activation of exhausted T cells

1. ABSTRACT CD8 ⁺ T cell exhaustion during chronic infection and cancer is marked by impaired effector function and limited responsiveness to stimulation. While memory CD8⁺ T cells can be activated TCR-independently by IL - 12 and IL - 18, it remains unclear whether exhausted cells, despite diminished TCR responsiveness, retain this cytokine-driven effector capacity. Here, we show that IL - 12 and IL - 18 stimulation induce robust IFNγ production in exhausted CD8 ⁺ T cells from chronic LCMV Cl13 infection, exceeding responses to antigen-specific stimulation. This activation does not result in upregulation of Tox, suggesting engagement of transcriptional circuits distinct from those promoting exhaustion. Single-cell transcriptomics revealed an innate acting T cell (T IA )-specific gene signature enriched within exhausted populations in chronic infection and tumor-infiltrating lymphocytes, particularly at the interface of intermediate and terminal exhaustion. Using heterologous Legionella pneumophila infection, we confirmed in vivo bystander responsiveness of exhausted CD8 ⁺ T cells, reducing bacterial burden, highlighting their functional capacity. Our findings demonstrate that exhausted CD8 ⁺ T cells retain inducible effector capacity through IL - 12 and IL - 18 stimulation, providing new insights into possible routes to activate exhausted T cells. Abstract Figure