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

Ryu Watanabe, Hiroshi Fujii, Tsuyoshi Shirai, Shinichiro Saito, Tomonori Ishii, Hideo Harigae

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

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 naïve 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 naïve 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.

Original languageEnglish
Pages (from-to)2508-2520
Number of pages13
JournalEuropean Journal of Immunology
Volume44
Issue number8
DOIs
Publication statusPublished - 2014 Aug

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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