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

Qian Hu,Yujie Xie,Xin Nie,Yong Zhao,Yuanlong Ge,Jun Tao

doi:10.1038/s41419-018-0649-z

Qian Hu, Yujie Xie + Show 4 more

Open Access

https://doi.org/10.1038/s41419-018-0649-z

Copy DOI

Abstract

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 γH2AX 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.

Highlights

Each human cell is challenged by over 105 DNA lesions that come from the environment and cellular metabolism every day[1]
We observed that there is no significant difference in the percentage of apoptotic cells between treatments with different doses (Fig. 1c), demonstrating that resting T cells are hypersensitive to double-stranded break (DSB)
Our results reveal that when facing DNA damage such as DSBs and single-stranded breaks (SSBs), resting and stimulated CD4+ T cells behave differently

Summary

Introduction

Each human cell is challenged by over 105 DNA lesions that come from the environment and cellular metabolism every day[1]. Human cells are equipped with DNA damage repair (DDR) machinery to address a variety of lesions[2]. DNA damage is first detected by ATM, ATR, which stimulate a DDR cascade. Various downstream proteins including CHK1, CHK2, and p53 are activated, leading to transient cell cycle arrest that provides time for DNA repair[3]. Ser[139] on H2AX is phosphorylated surrounding the damage site, forming a dock to recruit DDR-related proteins[4].

Methods

Results

Conclusion