Abstract
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.
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Abbreviations
- APC:
-
antigen-presenting cell
- DC:
-
dendritic cell
- DLN:
-
draining lymph node
- LC3-PE:
-
LC3-phosphatidylethanolamine
- MEF:
-
mouse embryonic fibroblast
- MOMP:
-
mitochondrial outer membrane permeabilization
- PCD:
-
programmed cell death
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Acknowledgements
This work was supported by grants from Mildred Scheel Stipendium, Deutsche Krebshilfe (MU), EMBO (OK), Ligue Nationale Contre le Cancer (MLA, GK), EURYI Scheme, European Science Foundation (MLA), Agence Nationale de la Recherche and Institut National Du Cancer (MLA and GK).
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Uhl, M., Kepp, O., Jusforgues-Saklani, H. et al. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ 16, 991–1005 (2009). https://doi.org/10.1038/cdd.2009.8
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DOI: https://doi.org/10.1038/cdd.2009.8
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