Resting T cells are hypersensitive to DNA damage due to defective DNA repair pathway.

Blood cells are challenged by intrinsic and exogenous stress that may result in many types of damage to DNA. As a major participant in cell-mediated immunity in blood, T lymphocytes are maintained in their quiescent (resting) state for most of their lives and switch to the proliferating state once stimulated. How resting and stimulated T cells address DNA damage remains largely unknown. Here, we report that while different types of DNA damage are efficiently repaired in stimulated T cells, they result in massive apoptosis of resting T cells. Mechanistically, DNA damage in resting T cells activates the ATM/ATR/DNA-PKcs signaling pathway but fails to induce the formation of γHAX and 53BP1 foci, leading to unrepaired DNA damage that activates apoptosis in a p53-independent but JNK/p73-dependent manner. Mice challenged with high DNA damage stress display far fewer T cells in peripheral blood, lymph nodes, and spleens. Collectively, these results reveal that resting T cells are hypersensitive to DNA damage due to defects in DNA damage repair mechanisms. These findings provide new insight into T-cell function and maintenance of immunity under highly stressed conditions.