NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death.

During the response to infections and pathogenic challenges, T cells must expand profoundly and be resilient to repetitive restimulation to clear the ongoing assault and protect the host. This process of prolific expansion is tightly regulated to quickly provide a robust pool of pathogen-fighting T cells, yet also limit excessive expansion to prevent inadvertent damage to host tissues. Restimulation-dependent pro-growth and pro-death signals help regulate this delicate balance of T cell expansion to maintain both host and T cell homeostasis. We have discovered that NDRG3 is a critical determinant of whether T cells proliferate or undergo apoptosis during repetitive restimulation under antigen-driven T cell expansion. CD8+ T cells lacking NDRG3 exhibit severely impaired expansion in vivo in response to both viral infections and tumor challenges. We show that NDRG3 is essential for T cell survival during antigen restimulation by protecting T cells from restimulation-induced cell death (RICD), while it has only a marginal impact on T cell survival in contexts with limited antigen restimulation. Mechanistically, NDRG3 safeguards repetitively stimulated T cells from RICD by constraining FAS-mediated pro-death signaling through caspase-8. Furthermore, NDRG3 overexpression enhanced T cell infiltration into tumors, improving their tumor-controlling capacity. Collectively, these findings establish NDRG3 as a novel, indispensable regulator of T cell responses to foreign challenges. Additionally, this work identifies NDRG3 as a previously undescribed regulator of RICD in T cells and reveals NDRG3 as a potential target for autoimmune disorders and chimeric antigen receptor T cell treatment for cancer.