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.
Uhl
M
M
Department of Immunology, Groupe Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France.
Kepp
O
O
Jusforgues-Saklani
H
H
Vicencio
J-M
JM
Kroemer
G
G
Albert
M L
ML
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D037282:Calreticulin / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000821:virology; D055785:Gene Knockdown Techniques; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D034741:RNA, Small Interfering / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C494773:Bak1 protein, mouse; D037282:Calreticulin; D007370:Interferon Type I; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein