Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection | Nature Immunology
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Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection

Nature Immunology volume 10, pages 480–487 (2009)Cite this article

Abstract

Viral proteins are usually processed by the 'classical' major histocompatibility complex (MHC) class I presentation pathway. Here we showed that although macrophages infected with herpes simplex virus type 1 (HSV-1) initially stimulated CD8+ T cells by this pathway, a second pathway involving a vacuolar compartment was triggered later during infection. Morphological and functional analyses indicated that distinct forms of autophagy facilitated the presentation of HSV-1 antigens on MHC class I molecules. One form of autophagy involved a previously unknown type of autophagosome that originated from the nuclear envelope. Whereas interferon-γ stimulated classical MHC class I presentation, fever-like hyperthermia and the pyrogenic cytokine interleukin 1β activated autophagy and the vacuolar processing of viral peptides. Viral peptides in autophagosomes were further processed by the proteasome, which suggests a complex interaction between the vacuolar and MHC class I presentation pathways.

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Figure 1: A vacuolar pathway participates in the processing of endogenous viral proteins for presentation on MHC class I molecules.
Figure 2: Autophagy induced during HSV-1 infection contributes to the processing and presentation of endogenous viral antigens on MHC class I molecules.
Figure 3: Both gB and LC3 accumulate in perinuclear regions during HSV-1 infection.
Figure 4: HSV-1 induces the formation of autophagosome-like structures from the nuclear envelopes of infected macrophages.
Figure 5: The four-layered membrane structures that emerge from the nuclear envelope have autophagosome-like features.
Figure 6: Involvement of lytic vacuolar compartments in the processing and presentation of endogenous antigens on MHC class I molecules after treatment with proinflammatory cytokines.

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Acknowledgements

We thank J. Thibodeau and C. Perreault for critical reading of the manuscript; K. Rock (University of Massachusetts Medical School) for BMA cells; W. Heath (University of Melbourne) for the HSV-2.3.2E2 hybridoma; G. Arthur (University of Manitoba) for the wild-type and Atg5−/− mouse embryonic fibroblasts produced by N. Mizushima (Medical and Dental University, Tokyo); P. Desai (Johns Hopkins University) for the HSV-1 K26-GFP mutant; and M. Bendayan for assistance with electron microscopy. Supported by the Canadian Institutes for Health Research (R.L. and M.D.), the Natural Science and Engineering Research Council of Canada (L.E.), Fonds de la Recherche en Santé du Québec (L.E.), the US National Institutes of Health (EY09083) and Research to Prevent Blindness (D.L.)

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Authors and Affiliations

  1. Département de Pathologie et Biologie Cellulaire, Université de Montréal, Succursale Centre-Ville, Montreal, Quebec, Canada

    Luc English, Magali Chemali, Johanne Duron, Christiane Rondeau, Annie Laplante, Diane Gingras, Roger Lippé & Michel Desjardins

  2. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA

    Diane Alexander & David Leib

  3. Department of Microbiology and Immunology, Pennsylvania State University, Milton S. Hershey College of Medicine, Hershey, Pennsylvania, USA

    Christopher Norbury

  4. Département de microbiologie et immunologie, Université de Montréal, Succursale Centre-Ville, Montreal, Quebec, Canada

    Michel Desjardins

  5. Caprion Pharmaceuticals, Montréal, Québec, Canada

    Michel Desjardins

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Contributions

L.E. planned and did most of the experiments and actively participated in writing the manuscript; M.C. did the experiments with mouse embryonic fibroblasts; J.D. maintained viral stocks; C.R. did the technical work for Epon electron microscopy; A.L. provided technical assistance for immunoblot analysis and immunofluorescence; D.G. did the immunogold labeling and morphological quantification; D.A. and D.L. produced the ICP34.5 HSV-1 mutant; C.N. participated in the planning and development of the antigen-presentation assay and provided help in writing the manuscript; R.L. provided HSV-1 virus stocks and expertise with the infection system and helped write the manuscript; and M.D. planned and directed the work and wrote the manuscript.

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Correspondence to Michel Desjardins.

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M.D. is a consultant for Caprion Pharmaceuticals for their program on brucella.

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English, L., Chemali, M., Duron, J. et al. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10, 480–487 (2009). https://doi.org/10.1038/ni.1720

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