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

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.