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

Cell Death Differ. 2009 Jul;16(7):991-1005. doi: 10.1038/cdd.2009.8. Epub 2009 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology*
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Autophagy / genetics
  • Autophagy / immunology*
  • Autophagy-Related Protein 5
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Calreticulin / immunology
  • Calreticulin / metabolism
  • Cross-Priming / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Gene Knockdown Techniques
  • Humans
  • Influenza A virus / immunology
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Lymphocyte Activation / immunology
  • Major Histocompatibility Complex / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / immunology
  • Microtubule-Associated Proteins / metabolism
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / virology
  • RNA, Small Interfering / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / immunology
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / immunology
  • bcl-2-Associated X Protein / metabolism


  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Bak1 protein, mouse
  • Calreticulin
  • Interferon Type I
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein