期刊
CELL DEATH AND DIFFERENTIATION
卷 16, 期 7, 页码 991-1005出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.8
关键词
cross-priming; autophagy; apoptosis; Atg5
资金
- Mildred Scheel Stipendium, Deutsche Krebshilfe
- EMBO
- Ligue Nationale Contre le Cancer
- EURYI Scheme, European Science Foundation
- Agence Nationale de la Recherche and Institut National Du Cancer
Cross-presentation of cell-associated antigen is important in the priming of CD8(+) 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(-/-) fibroblasts. We assessed virally infected WT and Bax/Bak(-/-) 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(+) 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(+) T cells. Cell Death and Differentiation (2009) 16, 991-1005; doi: 10.1038/cdd.2009.8; published online 20 February 2009
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