title: 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.
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.
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujii
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shirai
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Saito
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ishii
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology*; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005822:Genetic Vectors / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism
chemical_list: D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species
keywords: Apoptosis; Autophagy; Human T cell; Mitophagy; Reactive oxygen species