PI3Kdelta promotes T cell effector differentiation and plasticity during chronic infection

Pichler, A. C.; Cannons, J. L.; Golec, D. P.; Reilley, J. M.; Corral, D.; Ansaldo, E.; Xu, Q.; Paul, S.; Schaughency, P.; Otaizo-Carrasquero, F. P.; Anderson, S.; Deewan, A.; McGavern, D.; Schwartzberg, P. L.

doi:10.64898/2025.12.19.695585

bioRxiv · 10.64898/2025.12.19.695585

PI3Kdelta promotes T cell effector differentiation and plasticity during chronic infection

Pichler, A. C.·Cannons, J. L.·Golec, D. P.·Reilley, J. M.·Corral, D.·Ansaldo, E.·Xu, Q.·Paul, S.·Schaughency, P.·Otaizo-Carrasquero, F. P.·Anderson, S.·Deewan, A.·McGavern, D.·Schwartzberg, P. L.

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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 {delta} (PI3K{delta}) 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 PI3K{delta} 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 PI3K{delta} 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 PI3K{delta} 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.

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Pichler, A. C., Cannons, J. L., Golec, D. P., Reilley, J. M., Corral, D., Ansaldo, E., Xu, Q., Paul, S., Schaughency, P., Otaizo-Carrasquero, F. P., Anderson, S., Deewan, A., McGavern, D., Schwartzberg, P. L.. 2025-12-23. PI3Kdelta promotes T cell effector differentiation and plasticity during chronic infection. https://doi.org/10.64898/2025.12.19.695585

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