ATR kinase inhibitors induce mitochondrial fission in CD8+ T cells and impair immune memory in vivo

ATR kinase inhibitors were originally developed to potentiate chemotherapy-induced DNA damage at stalled replication forks and to disrupt DNA damage-induced cell cycle checkpoints. Recent evidence, however, reveals that these inhibitors also disrupt cell cycle organization in cells that have not sustained any DNA damage.

We show that ATR kinase inhibitors potently trigger unscheduled mitochondrial fission, causing loss of mitochondrial mass in actively dividing CD8+ T cells that persists in memory CD8+ T cells. Moreover, ATR inhibition during the peak of CD8+ T cell expansion in a mouse model of LCMV Armstrong infection impairs the formation of immune memory. These findings carry significant clinical implications.