Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery

Kovács, János; Li, C; Yang, Qin; Li, G; García, Ingrid; Ju, Songguang; Roodman, David; Windle, Jolene J.; Zhang, Xie; Lu, Binfeng

doi:10.1038/cdd.2011.78

Cited by 193 publications

(251 citation statements)

References 40 publications

(51 reference statements)

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“…Thus, to clarify the requirement of autophagy for T-cell homeostasis, it is useful to examine mice with mutations in genes lying upstream of Atg5 and Atg7 in the autophagy pathway, for example, genes encoding the class III PI3K complex (Vps34-Vps15-Beclin-1). Similar to Atg5 and Atg7 KO mice, mice with a T-cell-specific deletion of Beclin-1 (Cd4-CreBecn1 flox/flox mice) showed impaired T-cell homeostasis (19). In contrast, another study using Beclin-1-deficient mice derived from Rag1 blastocyst complementation reported a defect in T-cell development but a normal peripheral T-cell compartment (20).…”

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Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis

Willinger

Flavell²

2012

Proc. Natl. Acad. Sci. U.S.A.

155

148

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The homeostasis of naive T cells is essential for protective immunity against infection, but the cell-intrinsic molecular mechanisms that control naïve T-cell homeostasis are poorly understood. Genetic ablation in lower organisms has revealed a critical role for Vps34, an evolutionary conserved class III phosphoinositide-3 kinase (PI3K), in regulating endocytosis and autophagy; however, the physiological function of Vps34 in the immune system, especially in T cells, is unclear. Here we report that Vps34 is required for the maintenance of naïve T cells, acting in a cell-intrinsic manner. T-cell–specific deletion of the gene encoding Vps34 resulted in reduced stability of Vps15 and Beclin-1, components of the class III PI3K complex, and impaired autophagy in T cells. Vps34 was dispensable for T-cell development but important for the survival of naïve T cells. Vps34-deficient T cells showed increased mitochondrial mass and accumulation of reactive oxygen species, consistent with deficient removal of damaged mitochondria. Thus, Vps34-dependent canonical autophagy plays a critical role in maintaining T-cell homeostasis by promoting T-cell survival through quality control of mitochondria.

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mentioning

confidence: 94%

Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis

Willinger

Flavell²

2012

Proc. Natl. Acad. Sci. U.S.A.

155

148

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“…L'autophagie régule également le stress du réticulum endoplasmique (RE) en intervenant dans la dégradation sélective de ses membranes [22,23]. Enfin, elle permet le catabolisme de procaspases désensibilisant ainsi les cellules à l'apoptose [25]. Un rôle de l'autophagie dans la polarisation des cellules T auxiliaires (Th) a égale-ment été rapporté [22,23].…”

Section: Autophagie Et éDucation Des Lymphocytes Tunclassified

“…Un rôle de l'autophagie dans la polarisation des cellules T auxiliaires (Th) a égale-ment été rapporté [22,23]. En effet, elle apparaît plus importante pour la survie des cellules Th1, Th2 et Th0 que pour celle des cellules Th17 [25] avec une plus forte induction dans les cellules Th2 que dans les cellules Th1 [26]. Dans tous les cas, des variations de métabolisme et de sensibilité à l'apoptose entre les différents types de cellules Th, pourraient être à l'origine de ce besoin différentiel en autophagie.…”

Section: Autophagie Et éDucation Des Lymphocytes Tunclassified

“…L'autophagie permet également de soutenir la demande métabolique en générant des acides aminés (AA) [24]. Enfin, elle permet de dégrader les pro-caspases [25]. Les cellules Th (T helper) peuvent se différencier en plusieurs sous-types.…”

Section: Le Rôle De L'autophagie Dans La Survie Et L'activation Des Lunclassified

“…La première étude s'intéressant à l'activité autophagique des lymphocytes lors de dysfonctionnements immunitaires décrit une augmentation de l'expression de la protéine ATG5 dans les LT qui infiltrent les lésions observées dans la sclérose en plaques (SEP) [41]. L'absence d'autophagie dans les LT diminue ainsi les symptômes de la pathologie dans un modèle murin de SEP [25], l'amélioration clinique étant liée à une baisse du nombre de lymphocytes de type Th1. Dans une pathologie auto-immune systémique -le lupus érythémateux disséminé (LED) 6 -, l'identification de polymorphismes génétiques dans la région du gène ATG5, corrélés avec le développement de la pathologie, a conduit à s'interroger sur l'implication de l'autophagie [42].…”

Section: Autophagie Des Lymphocytes Et Physiopathologieunclassified

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L’autophagie et l’homéostasie des lymphocytes T et B

et al. 2016

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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

et al. 2014

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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 autophagydefective 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.Keywords: Apoptosis r Autophagy r Human T cell r Mitophagy r Reactive oxygen speciesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy (hereafter referred to as autophagy) is an evolutionally conserved intracellular degradation system. During autophagy, a small vesicle known as a sequestering phagophore or an isolation membrane engulfs cytoplasmic materials and organelles to form a double membrane structure, an autophagosome. The autophagosome subsequently fuses with a lysoCorrespondence: Dr. Hiroshi Fujii e-mail: hfujii@med.tohoku.ac.jp some to become an autolysosome, leading to degradation of the enclosed materials for recycling or energy production [1]. Autophagy is activated in response to nutrient starvation and various cellular stresses such as hypoxia, ER stress, and pharmacological treatment. Basal levels of autophagy under nutrientsufficient conditions act as a quality control mechanism to degrade damaged organelles or aggregated proteins [2]. Autophagy is considered to be involved in a wide range of normal physiological processes, whereas its dysregulation may contribute to the pathogenesis of numerous diseases such as neurodegeneration, Crohn's disease, infections, and cancers [3].C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2508-2520 New technology 2509Autophagy involves a set of gene products, termed Atg proteins [2]. Unc-51-like kinase 1 (ULK1), which is a mammalian homolog of Atg1, initiates autophagosome formation. Subsequently, Atg9 and the Atg12-Atg5-Atg16 complex provide membranes required for elongation, after which Atg8 is incorporated into autophagosomes [4]. ULK...

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Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery

Cited by 193 publications

References 40 publications

Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis

Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis

L’autophagie et l’homéostasie des lymphocytes T et B

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

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