Autophagy plays a protective role as an anti-oxidant system in human T cells and represents a novel strategy for induction of T-cell apoptosis

作者：Watanabe Ryu; Fujii Hiroshi^*; Shirai Tsuyoshi; Saito Shinichiro; Ishii Tomonori; Harigae Hideo

来源：European Journal of Immunology, 2014, 44(8): 2508-2520.

DOI：10.1002/eji.201344248

• Apoptosis
• Autophagy
• Human T cell
• Mitophagy
• Reactive oxygen species

Autophagy is an intracellular degradation system that plays an important role in T-cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP-LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy-defective naive CD4(+)T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy-defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4(+) T cells had lower autophagic activity than naive CD4(+) T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti-oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T-cell death, which could be a novel strategy for induction of T-cell apoptosis.

• 出版日期2014-8