PI3Kδ promotes T cell effector differentiation and plasticity during chronic infection

Abstract Persistent antigen exposure in chronic infections and cancer leads to a progressive state of T cell dysfunction known as exhaustion, which represents a major barrier to effective immune control, but allows antigen-specific T cells to persist. Understanding signaling pathways that mitigate exhaustion and reinvigorate CD8+ T cell effector function is a key goal for immunotherapeutic strategies. Here, we show that an activating mutant of phosphoinositide-3-kinase δ (PI3Kδ) led to a reduction of FoxO1-dependent TCF-1+ stem-like progenitor CD8+ T cells that are required for sustaining antigen-specific T cells in response to chronic viral infection. Nonetheless, mice expressing activated PI3Kδ maintained CD8+ T cell responses that were skewed instead towards effector-like cells in a FoxO1-independent manner, associated with an amplified IL-21-STAT3 response axis and improved viral control. Activated PI3Kδ limited TOX expression, prevented epigenetic changes associated with T cell exhaustion, and promoted effector differentiation and function from both progenitor stem-like cells and cells with an exhausted phenotype. Together, this work uncovers a key role for PI3Kδ activation in shaping the balance and plasticity between effector function and exhaustion while promoting T cell persistence during chronic infection, providing insight for immunotherapeutic strategies. Competing Interest Statement The authors have declared no competing interest.