Innate and Adaptive Immunity through Autophagy

Schmid, Dorothee; Münz, Christian

doi:10.1016/j.immuni.2007.07.004

Cited by 376 publications

(321 citation statements)

References 109 publications

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“…However, some pathogens have the capacity to subvert autophagic processes as a strategy for increasing intracellular survival. 23,40 In this study, we evaluated whether autophagy might occur in gastric epithelial cells exposed to the gastric pathogen H. pylori, for which persistent infection is a risk factor for the onset of gastric cancer. 3 VacA-dependent vacuoles were still present in Atg12 knockdown cells, as visibly evident using microscopy (vacuoles were still present in >50% of the cells; Fig.…”

Section: Discussionmentioning

confidence: 99%

Effect ofHelicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells

et al. 2009

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Section: Discussionmentioning

confidence: 99%

Effect ofHelicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells

et al. 2009

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“…48,49 Indeed, there is strong evidence that viral, tumor and self-antigens may gain access to the MHC II processing pathway by entry into autophagosomes. 50 This pathway constitutes a mechanism by which endogenous proteins may access the 'classical' exogenous MHC II pathway. Thus far, macroautophagy and chaperone-mediated autophagy have been shown to have a function in the delivery of cytosolic antigen to the MHC II processing.…”

Section: Discussionmentioning

confidence: 99%

Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells

et al. 2009

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Cross-presentation of cell-associated antigen is important in the priming of CD8 þ T-cell responses to proteins that are not expressed by antigen-presenting cells (APCs). In vivo, dendritic cells are the main cross-presenting APC, and much is known regarding their ability to capture and process cell-associated antigen. In contrast, little is known about the way death effector pathways influence the efficiency of cross-priming. Here, we compared two important mechanisms of programmed cell death: classical apoptosis, as it occurs in wild-type (WT) fibroblasts, and caspase-independent cell death, which occurs with increased features of autophagy in Bax/Bak À/À fibroblasts. We assessed virally infected WT and Bax/Bak À/À fibroblasts as a source of cell-associated antigen. We found that immunization with cells undergoing autophagy before cell death was superior in facilitating the cross-priming of antigen-specific CD8 þ T cells. Strikingly, silencing of Atg5 expression inhibited priming. We interpret this to be a novel form of 'immunogenic death' with the enhanced priming efficiency being a result of persistent MHC I cross-presentation and the induction of type I interferons. These results offer the first molecular evidence that catabolic pathways, including autophagy, influence the efficiency of cross-priming. We predict that targeting the autophagy cascade may provide a therapeutic strategy for achieving robust cross-priming of viral and tumor-specific CD8 þ T cells. There is now evidence to suggest that antigen-presenting cells (APCs) have evolved mechanisms to capture immunologically relevant information from internalized apoptotic cells, thus offering a mechanism whereby cell death may influence subsequent immune response(s). 1-3 Specifically, it has been shown that antigen derived from phagocytosed dying cells may be processed by dendritic cells (DCs) to generate MHC I/peptide, resulting in the activation of CD8 þ T cells. This pathway is called crosspriming due to the 'crossing' of the classically defined restriction of MHC I for presentation of endogenously synthesized protein. 4 In addition, dying cells are also capable of skewing cytokine production in phagocytes. 5 For example, macrophages and DCs engulf dying cells through specific phagocytic receptors (e.g., CD36, a v b 5 , CR3 and others), which may result in the inhibition of proinflammatory cytokine secretion (e.g., IL-1b, IL-12 and TNF-a). [6][7][8][9] These studies have all addressed the downstream effects of dying cells on the immune system with little attention to the complexity of cell death pathways. We hypothesized that the molecular mechanism of cell death influences the immunologic instruction given to the phagocyte and we focused our attention on two of the major classes of PCD that have been described: type I PCD (or classical apoptosis) and type II PCD (referred to as autophagic cell death or caspase-independent cell death). 10 Distinct, yet intertwined pathways are involved in executing cell death programs. Briefly, apoptosis is mediated ...

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“…Recent data suggest that regulated autophagy is important for naïve T-cell homeostasis (10)(11)(12)(13). For example, T cells from Atg3, Atg5, and Atg7 KO mice have shown increased apoptosis and impaired TCR-induced proliferation in vitro (14)(15)(16)(17)(18).…”

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confidence: 99%

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.

153

137

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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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Innate and Adaptive Immunity through Autophagy

Cited by 376 publications

References 109 publications

Effect ofHelicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells

Effect ofHelicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells

Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells

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

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