Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2012 Nov 8;3(12):911–920. doi: 10.1007/s13238-012-2097-3

Intersection of autophagy with pathways of antigen presentation

Natalie L Patterson 1, Justine D Mintern 1,
PMCID: PMC4875384  PMID: 23136066

Abstract

Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

Keywords: autophagy, antigen presentation, antigen presenting cells, dendritic cells, MHCI, MHCII

References

  1. Anand P.K., Tait S.W., Lamkanfi M., Amer A.O., Nunez G., Pages G., Pouyssegur J., McGargill M.A., Green D.R., Kanneganti T.D. TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation. J Biol Chem. 2011;286:42981–42991. doi: 10.1074/jbc.M111.310599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baba M., Takeshige K., Baba N., Ohsumi Y. Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J Cell Biol. 1994;124:903–913. doi: 10.1083/jcb.124.6.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Benko S., Philpott D.J., Girardin S.E. The microbial and danger signals that activate Nod-like receptors. Cytokine. 2008;43:368–373. doi: 10.1016/j.cyto.2008.07.013. [DOI] [PubMed] [Google Scholar]
  4. Bevan M.J. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med. 1976;143:1283–1288. doi: 10.1084/jem.143.5.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blommaart E.F., Krause U., Schellens J.P., Vreeling-Sindelarova H., Meijer A.J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem. 1997;243:240–246. doi: 10.1111/j.1432-1033.1997.0240a.x. [DOI] [PubMed] [Google Scholar]
  6. Burman C., Ktistakis N.T. Regulation of autophagy by phosphatidylinositol 3-phosphate. FEBS Lett. 2010;584:1302–1312. doi: 10.1016/j.febslet.2010.01.011. [DOI] [PubMed] [Google Scholar]
  7. Comber J.D., Robinson T.M., Siciliano N.A., Snook A.E., Eisenlohr L.C. Functional macroautophagy induction by influenza A virus without a contribution to major histocompatibility complex class II-restricted presentation. J Virol. 2011;85:6453–6463. doi: 10.1128/JVI.02122-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cooney R., Baker J., Brain O., Danis B., Pichulik T., Allan P., Ferguson D.J., Campbell B.J., Jewell D., Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–97. doi: 10.1038/nm.2069. [DOI] [PubMed] [Google Scholar]
  9. De Luca A., Iannitti R.G., Bozza S., Beau R., Casagrande A., D’Angelo C., Moretti S., Cunha C., Giovannini G., Massi-Benedetti C., et al. CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J Clin Invest. 2012;122:1816–1831. doi: 10.1172/JCI60862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Delgado M.A., Elmaoued R.A., Davis A.S., Kyei G., Deretic V. Toll-like receptors control autophagy. EMBO J. 2008;27:1110–1121. doi: 10.1038/emboj.2008.31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dengjel J., Schoor O., Fischer R., Reich M., Kraus M., Muller M., Kreymborg K., Altenberend F., Brandenburg J., Kalbacher H., et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A. 2005;102:7922–7927. doi: 10.1073/pnas.0501190102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dorfel D., Appel S., Grunebach F., Weck M.M., Muller M.R., Heine A., Brossart P. Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro-transcribed MUC1 RNA. Blood. 2005;105:3199–3205. doi: 10.1182/blood-2004-09-3556. [DOI] [PubMed] [Google Scholar]
  13. English L., Chemali M., Duron J., Rondeau C., Laplante A., Gingras D., Alexander D., Leib D., Norbury C., Lippe R., et al. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol. 2009;10:480–487. doi: 10.1038/ni.1720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gutierrez M.G., Master S.S., Singh S.B., Taylor G.A., Colombo M.I., Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119:753–766. doi: 10.1016/j.cell.2004.11.038. [DOI] [PubMed] [Google Scholar]
  15. Hara T., Takamura A., Kishi C., Iemura S., Natsume T., Guan J.L., Mizushima N. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol. 2008;181:497–510. doi: 10.1083/jcb.200712064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Harris J., De Haro S.A., Master S.S., Keane J., Roberts E.A., Delgado M., Deretic V. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity. 2007;27:505–517. doi: 10.1016/j.immuni.2007.07.022. [DOI] [PubMed] [Google Scholar]
  17. Jagannath C., Lindsey D.R., Dhandayuthapani S., Xu Y., Hunter R.L., Jr., Eissa N.T. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15:267–276. doi: 10.1038/nm.1928. [DOI] [PubMed] [Google Scholar]
  18. Jia W., He Y.W. Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J Immunol. 2011;186:5313–5322. doi: 10.4049/jimmunol.1002404. [DOI] [PubMed] [Google Scholar]
  19. Joffre O.P., Segura E., Savina A., Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012;12:557–569. doi: 10.1038/nri3254. [DOI] [PubMed] [Google Scholar]
  20. Johnstone, C., Ramos, M., Garcia-Barreno, B., Lopez, D., Melero, J.A., and Del Val, M. (2012). Exogenous, TAP-independent lysosomal presentation of a respiratory syncytial virus CTL epitope. Immunol Cell Biol. (In Press). [DOI] [PubMed]
  21. Jung C.H., Jun C.B., Ro S.H., Kim Y.M., Otto N.M., Cao J., Kundu M., Kim D.H. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20:1992–2003. doi: 10.1091/mbc.E08-12-1249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jung C.H., Ro S.H., Cao J., Otto N.M., Kim D.H. mTOR regulation of autophagy. FEBS Lett. 2010;584:1287–1295. doi: 10.1016/j.febslet.2010.01.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kabeya Y., Mizushima N., Ueno T., Yamamoto A., Kirisako T., Noda T., Kominami E., Ohsumi Y., Yoshimori T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J. 2000;19:5720–5728. doi: 10.1093/emboj/19.21.5720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kasai M., Tanida I., Ueno T., Kominami E., Seki S., Ikeda T., Mizuochi T. Autophagic compartments gain access to the MHC class II compartments in thymic epithelium. J Immunol. 2009;183:7278–7285. doi: 10.4049/jimmunol.0804087. [DOI] [PubMed] [Google Scholar]
  25. Klionsky D.J., Cregg J.M., Dunn W.A., Jr., Emr S.D., Sakai Y., Sandoval I.V., Sibirny A., Subramani S., Thumm M., Veenhuis M., et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5:539–545. doi: 10.1016/S1534-5807(03)00296-X. [DOI] [PubMed] [Google Scholar]
  26. Klionsky D.J., Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol. 1999;15:1–32. doi: 10.1146/annurev.cellbio.15.1.1. [DOI] [PubMed] [Google Scholar]
  27. Komatsu M., Waguri S., Ueno T., Iwata J., Murata S., Tanida I., Ezaki J., Mizushima N., Ohsumi Y., Uchiyama Y., et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169:425–434. doi: 10.1083/jcb.200412022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kuma A., Hatano M., Matsui M., Yamamoto A., Nakaya H., Yoshimori T., Ohsumi Y., Tokuhisa T., Mizushima N. The role of autophagy during the early neonatal starvation period. Nature. 2004;432:1032–1036. doi: 10.1038/nature03029. [DOI] [PubMed] [Google Scholar]
  29. Lee H.K., Mattei L.M., Steinberg B.E., Alberts P., Lee Y.H., Chervonsky A., Mizushima N., Grinstein S., Iwasaki A. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity. 2010;32:227–239. doi: 10.1016/j.immuni.2009.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Levine B., Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42. doi: 10.1016/j.cell.2007.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Li B., Lei Z., Lichty B.D., Li D., Zhang G.M., Feng Z.H., Wan Y., Huang B. Autophagy facilitates major histocompatibility complex class I expression induced by IFN-gamma in B16 melanoma cells. Cancer Immunol Immunother. 2010;59:313–321. doi: 10.1007/s00262-009-0752-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Li H., Li Y., Jiao J., Hu H.M. Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nature nanotechnology. 2011;6:645–650. doi: 10.1038/nnano.2011.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Li W., Yang Q., Mao Z. Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci. 2011;68:749–763. doi: 10.1007/s00018-010-0565-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Li Y., Wang L.X., Yang G., Hao F., Urba W.J., Hu H.M. Efficient cross-presentation depends on autophagy in tumor cells. Cancer research. 2008;68:6889–6895. doi: 10.1158/0008-5472.CAN-08-0161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McLeod I.X., Zhou X., Li Q.J., Wang F., He Y.W. The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Ralpha surface expression. J Immunol. 2011;187:5051–5061. doi: 10.4049/jimmunol.1100710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mintern J.D., Villadangos J.A. Autophagy and mechanisms of effective immunity. Front Immunol. 2012;3:60. doi: 10.3389/fimmu.2012.00060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mizushima N., Noda T., Yoshimori T., Tanaka Y., Ishii T., George M.D., Klionsky D.J., Ohsumi M., Ohsumi Y. A protein conjugation system essential for autophagy. Nature. 1998;395:395–398. doi: 10.1038/26506. [DOI] [PubMed] [Google Scholar]
  38. Mizushima N., Yamamoto A., Matsui M., Yoshimori T., Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15:1101–1111. doi: 10.1091/mbc.E03-09-0704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nedjic J., Aichinger M., Emmerich J., Mizushima N., Klein L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature. 2008;455:396–400. doi: 10.1038/nature07208. [DOI] [PubMed] [Google Scholar]
  40. Nimmerjahn F., Milosevic S., Behrends U., Jaffee E.M., Pardoll D.M., Bornkamm G.W., Mautner J. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur J Immunol. 2003;33:1250–1259. doi: 10.1002/eji.200323730. [DOI] [PubMed] [Google Scholar]
  41. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2001;2:211–216. doi: 10.1038/35056522. [DOI] [PubMed] [Google Scholar]
  42. Orenstein S.J., Cuervo A.M. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol. 2010;21:719–726. doi: 10.1016/j.semcdb.2010.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Orsi A., Razi M., Dooley H.C., Robinson D., Weston A.E., Collinson L.M., Tooze S.A. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell. 2012;23:1860–1873. doi: 10.1091/mbc.E11-09-0746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Paludan C., Schmid D., Landthaler M., Vockerodt M., Kube D., Tuschl T., Munz C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science. 2005;307:593–596. doi: 10.1126/science.1104904. [DOI] [PubMed] [Google Scholar]
  45. Poyet J.L., Srinivasula S.M., Tnani M., Razmara M., Fernandes-Alnemri T., Alnemri E.S. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem. 2001;276:28309–28313. doi: 10.1074/jbc.C100250200. [DOI] [PubMed] [Google Scholar]
  46. Qu X., Zou Z., Sun Q., Luby-Phelps K., Cheng P., Hogan R.N., Gilpin C., Levine B. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell. 2007;128:931–946. doi: 10.1016/j.cell.2006.12.044. [DOI] [PubMed] [Google Scholar]
  47. Riedel A., Nimmerjahn F., Burdach S., Behrends U., Bornkamm G.W., Mautner J. Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1-mediated nuclear export. Eur J Immunol. 2008;38:2090–2095. doi: 10.1002/eji.200737900. [DOI] [PubMed] [Google Scholar]
  48. Saitoh T., Fujita N., Hayashi T., Takahara K., Satoh T., Lee H., Matsunaga K., Kageyama S., Omori H., Noda T., et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A. 2009;106:20842–20846. doi: 10.1073/pnas.0911267106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Saitoh T., Fujita N., Jang M.H., Uematsu S., Yang B.G., Satoh T., Omori H., Noda T., Yamamoto N., Komatsu M., et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264–268. doi: 10.1038/nature07383. [DOI] [PubMed] [Google Scholar]
  50. Sanjuan M.A., Dillon C.P., Tait S.W., Moshiach S., Dorsey F., Connell S., Komatsu M., Tanaka K., Cleveland J.L., Withoff S., et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007;450:1253–1257. doi: 10.1038/nature06421. [DOI] [PubMed] [Google Scholar]
  51. Schmid D., Pypaert M., Munz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 2007;26:79–92. doi: 10.1016/j.immuni.2006.10.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Seglen P.O., Gordon P.B. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A. 1982;79:1889–1892. doi: 10.1073/pnas.79.6.1889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Segura E., Villadangos J.A. A modular and combinatorial view of the antigen cross-presentation pathway in dendritic cells. Traffic. 2011;12:1677–1685. doi: 10.1111/j.1600-0854.2011.01254.x. [DOI] [PubMed] [Google Scholar]
  54. Shintani T., Mizushima N., Ogawa Y., Matsuura A., Noda T., Ohsumi Y. Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. Embo J. 1999;18:5234–5241. doi: 10.1093/emboj/18.19.5234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sou Y.S., Waguri S., Iwata J., Ueno T., Fujimura T., Hara T., Sawada N., Yamada A., Mizushima N., Uchiyama Y., et al. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell. 2008;19:4762–4775. doi: 10.1091/mbc.E08-03-0309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sukseree S., Mildner M., Rossiter H., Pammer J., Zhang C.F., Watanapokasin R., Tschachler E., Eckhart L. Autophagy in the thymic epithelium is dispensable for the development of self-tolerance in a novel mouse model. PLoS One. 2012;7:e38933. doi: 10.1371/journal.pone.0038933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Suzuki K., Ohsumi Y. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 2007;581:2156–2161. doi: 10.1016/j.febslet.2007.01.096. [DOI] [PubMed] [Google Scholar]
  58. Suzuki T., Franchi L., Toma C., Ashida H., Ogawa M., Yoshikawa Y., Mimuro H., Inohara N., Sasakawa C., Nunez G. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 2007;3:e111. doi: 10.1371/journal.ppat.0030111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Takeda K., Kaisho T., Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376. doi: 10.1146/annurev.immunol.21.120601.141126. [DOI] [PubMed] [Google Scholar]
  60. Tanida I., Ueno T., Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36:2503–2518. doi: 10.1016/j.biocel.2004.05.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Tey S.K., Khanna R. Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway. Blood. 2012;120:994–1004. doi: 10.1182/blood-2012-01-402404. [DOI] [PubMed] [Google Scholar]
  62. Travassos L.H., Carneiro L.A., Ramjeet M., Hussey S., Kim Y.G., Magalhaes J.G., Yuan L., Soares F., Chea E., Le Bourhis L., et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55–62. doi: 10.1038/ni.1823. [DOI] [PubMed] [Google Scholar]
  63. Uhl M., Kepp O., Jusforgues-Saklani H., Vicencio J.M., Kroemer G., Albert M.L. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell death and differentiation. 2009;16:991–1005. doi: 10.1038/cdd.2009.8. [DOI] [PubMed] [Google Scholar]
  64. Weidberg H., Shvets E., Elazar Z. Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem. 2011;80:125–156. doi: 10.1146/annurev-biochem-052709-094552. [DOI] [PubMed] [Google Scholar]
  65. Willinger T., Flavell R.A. Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proc Natl Acad Sci U S A. 2012;109:8670–8675. doi: 10.1073/pnas.1205305109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Xu Y., Jagannath C., Liu X.D., Sharafkhaneh A., Kolodziejska K.E., Eissa N.T. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007;27:135–144. doi: 10.1016/j.immuni.2007.05.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yang Z., Klionsky D.J. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–822. doi: 10.1038/ncb0910-814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhou D., Li P., Lin Y., Lott J.M., Hislop A.D., Canaday D.H., Brutkiewicz R.R., Blum J.S. Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity. 2005;22:571–581. doi: 10.1016/j.immuni.2005.03.009. [DOI] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES