Intersection of autophagy with pathways of antigen presentation

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., and Kanneganti, T.D. (2011). TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation. J Biol Chem 286, 42981-42991 .10.1074/jbc.M111.310599
[2] Baba, M., Takeshige, K., Baba, N., and Ohsumi, Y. (1994). Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J Cell Biol 124, 903-913 .10.1083/jcb.124.6.903
[3] Benko, S., Philpott, D.J., and Girardin, S.E. (2008). The microbial and danger signals that activate Nod-like receptors. Cytokine 43, 368-373 .10.1016/j.cyto.2008.07.013
[4] Bevan, M.J. (1976). 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 143, 1283-1288 .10.1084/jem.143.5.1283
[5] Blommaart, E.F., Krause, U., Schellens, J.P., Vreeling-Sindelarova, H., and Meijer, A.J. (1997). The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243, 240-246 .10.1111/j.1432-1033.1997.0240a.x
[6] Burman, C., and Ktistakis, N.T. (2010). Regulation of autophagy by phosphatidylinositol 3-phosphate. FEBS Lett 584, 1302-1312 .10.1016/j.febslet.2010.01.011
[7] Comber, J.D., Robinson, T.M., Siciliano, N.A., Snook, A.E., and Eisenlohr, L.C. (2011). Functional macroautophagy induction by influenza A virus without a contribution to major histocompatibility complex class II-restricted presentation. J Virol 85, 6453-6463 .10.1128/JVI.02122-10
[8] Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D.J., Campbell, B.J., Jewell, D., and Simmons, A. (2010). NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16, 90-97 .10.1038/nm.2069
[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., . (2012). CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J Clin Invest 122, 1816-1831 .10.1172/JCI60862
[10] Delgado, M.A., Elmaoued, R.A., Davis, A.S., Kyei, G., and Deretic, V. (2008). Toll-like receptors control autophagy. EMBO J 27, 1110-1121 .10.1038/emboj.2008.31
[11] Dengjel, J., Schoor, O., Fischer, R., Reich, M., Kraus, M., Muller, M., Kreymborg, K., Altenberend, F., Brandenburg, J., Kalbacher, H., . (2005). Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A 102, 7922-7927 .10.1073/pnas.0501190102
[12] Dorfel, D., Appel, S., Grunebach, F., Weck, M.M., Muller, M.R., Heine, A., and Brossart, P. (2005). Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro-transcribed MUC1 RNA. Blood 105, 3199-3205 .10.1182/blood-2004-09-3556
[13] English, L., Chemali, M., Duron, J., Rondeau, C., Laplante, A., Gingras, D., Alexander, D., Leib, D., Norbury, C., Lippe, R., . (2009). Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10, 480-487 .10.1038/ni.1720
[14] Gutierrez, M.G., Master, S.S., Singh, S.B., Taylor, G.A., Colombo, M.I., and Deretic, V. (2004). Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753-766 .10.1016/j.cell.2004.11.038
[15] Hara, T., Takamura, A., Kishi, C., Iemura, S., Natsume, T., Guan, J.L., and Mizushima, N. (2008). FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181, 497-510 .10.1083/jcb.200712064
[16] Harris, J., De Haro, S.A., Master, S.S., Keane, J., Roberts, E.A., Delgado, M., and Deretic, V. (2007). T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27, 505-517 .10.1016/j.immuni.2007.07.022
[17] Jagannath, C., Lindsey, D.R., Dhandayuthapani, S., Xu, Y., Hunter, R.L., Jr., and Eissa, N.T. (2009). Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15, 267-276 .10.1038/nm.1928
[18] Jia, W., and He, Y.W. (2011). Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J Immunol 186, 5313-5322 .10.4049/jimmunol.1002404
[19] Joffre, O.P., Segura, E., Savina, A., and Amigorena, S. (2012). Cross-presentation by dendritic cells. Nat Rev Immunol 12, 557-569 .10.1038/nri3254
[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).10.1038/icb.2012.43
[21] Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., Kundu, M., and Kim, D.H. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20, 1992-2003 .10.1091/mbc.E08-12-1249
[22] Jung, C.H., Ro, S.H., Cao, J., Otto, N.M., and Kim, D.H. (2010). mTOR regulation of autophagy. FEBS Lett 584, 1287-1295 .10.1016/j.febslet.2010.01.017
[23] Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., and Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J 19, 5720-5728 .10.1093/emboj/19.21.5720
[24] Kasai, M., Tanida, I., Ueno, T., Kominami, E., Seki, S., Ikeda, T., and Mizuochi, T. (2009). Autophagic compartments gain access to the MHC class II compartments in thymic epithelium. J Immunol 183, 7278-7285 .10.4049/jimmunol.0804087
[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., . (2003). A unified nomenclature for yeast autophagy-related genes. Dev Cell 5, 539-545 .10.1016/S1534-5807(03)00296-X
[26] Klionsky, D.J., and Ohsumi, Y. (1999). Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 15, 1-32 .10.1146/annurev.cellbio.15.1.1
[27] Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., . (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169, 425-434 .10.1083/jcb.200412022
[28] Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., and Mizushima, N. (2004). The role of autophagy during the early neonatal starvation period. Nature 432, 1032-1036 .10.1038/nature03029
[29] Lee, H.K., Mattei, L.M., Steinberg, B.E., Alberts, P., Lee, Y.H., Chervonsky, A., Mizushima, N., Grinstein, S., and Iwasaki, A. (2010). In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32, 227-239 .10.1016/j.immuni.2009.12.006
[30] Levine, B., and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132, 27-42 .10.1016/j.cell.2007.12.018
[31] Li, B., Lei, Z., Lichty, B.D., Li, D., Zhang, G.M., Feng, Z.H., Wan, Y., and Huang, B. (2010). Autophagy facilitates major histocompatibility complex class I expression induced by IFN-gamma in B16 melanoma cells. Cancer Immunol Immunother 59, 313-321 .
[32] Li, H., Li, Y., Jiao, J., and Hu, H.M. (2011a). Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nature nanotechnology 6, 645-650 .10.1038/nnano.2011.153
[33] Li, W., Yang, Q., and Mao, Z. (2011b). Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci 68, 749-763 .10.1007/s00018-010-0565-6
[34] Li, Y., Wang, L.X., Yang, G., Hao, F., Urba, W.J., and Hu, H.M. (2008). Efficient cross-presentation depends on autophagy in tumor cells. Cancer research 68, 6889-6895 .10.1158/0008-5472.CAN-08-0161
[35] McLeod, I.X., Zhou, X., Li, Q.J., Wang, F., and He, Y.W. (2011). The class III kinase Vps34 promotes T lymphocyte survival through regulating IL-7Ralpha surface expression. J Immunol 187, 5051-5061 .10.4049/jimmunol.1100710
[36] Mintern, J.D., and Villadangos, J.A. (2012). Autophagy and mechanisms of effective immunity. Front Immunol 3, 60.10.3389/fimmu.2012.00060
[37] Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M., and Ohsumi, Y. (1998). A protein conjugation system essential for autophagy. Nature 395, 395-398 .10.1038/26506
[38] Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., and Ohsumi, Y. (2004). In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15, 1101-1111 .10.1091/mbc.E03-09-0704
[39] Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N., and Klein, L. (2008). Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396-400 .10.1038/nature07208
[40] Nimmerjahn, F., Milosevic, S., Behrends, U., Jaffee, E.M., Pardoll, D.M., Bornkamm, G.W., and Mautner, J. (2003). Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur J Immunol 33, 1250-1259 .10.1002/eji.200323730
[41] Ohsumi, Y. (2001). Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2, 211-216 .10.1038/35056522
[42] Orenstein, S.J., and Cuervo, A.M. (2010). Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 21, 719-726 .10.1016/j.semcdb.2010.02.005
[43] Orsi, A., Razi, M., Dooley, H.C., Robinson, D., Weston, A.E., Collinson, L.M., and Tooze, S.A. (2012). Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23, 1860-1873 .10.1091/mbc.E11-09-0746
[44] Paludan, C., Schmid, D., Landthaler, M., Vockerodt, M., Kube, D., Tuschl, T., and Munz, C. (2005). Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593-596 .10.1126/science.1104904
[45] Poyet, J.L., Srinivasula, S.M., Tnani, M., Razmara, M., Fernandes-Alnemri, T., and Alnemri, E.S. (2001). Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem 276, 28309-28313 .10.1074/jbc.C100250200
[46] Qu, X., Zou, Z., Sun, Q., Luby-Phelps, K., Cheng, P., Hogan, R.N., Gilpin, C., and Levine, B. (2007). Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931-946 .10.1016/j.cell.2006.12.044
[47] Riedel, A., Nimmerjahn, F., Burdach, S., Behrends, U., Bornkamm, G.W., and Mautner, J. (2008). Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1-mediated nuclear export. Eur J Immunol 38, 2090-2095 .10.1002/eji.200737900
[48] Saitoh, T., Fujita, N., Hayashi, T., Takahara, K., Satoh, T., Lee, H., Matsunaga, K., Kageyama, S., Omori, H., Noda, T., . (2009). Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A 106, 20842-20846 .10.1073/pnas.0911267106
[49] Saitoh, T., Fujita, N., Jang, M.H., Uematsu, S., Yang, B.G., Satoh, T., Omori, H., Noda, T., Yamamoto, N., Komatsu, M., . (2008). Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264-268 .10.1038/nature07383
[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., . (2007). Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257 .10.1038/nature06421
[51] Schmid, D., Pypaert, M., and Munz, C. (2007). Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26, 79-92 .10.1016/j.immuni.2006.10.018
[52] Seglen, P.O., and Gordon, P.B. (1982). 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A 79, 1889-1892 .10.1073/pnas.79.6.1889
[53] Segura, E., and Villadangos, J.A. (2011). A modular and combinatorial view of the antigen cross-presentation pathway in dendritic cells. Traffic 12, 1677-1685 .10.1111/j.1600-0854.2011.01254.x
[54] Shintani, T., Mizushima, N., Ogawa, Y., Matsuura, A., Noda, T., and Ohsumi, Y. (1999). Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. Embo J 18, 5234-5241 .10.1093/emboj/18.19.5234
[55] Sou, Y.S., Waguri, S., Iwata, J., Ueno, T., Fujimura, T., Hara, T., Sawada, N., Yamada, A., Mizushima, N., Uchiyama, Y., . (2008). The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell 19, 4762-4775 .10.1091/mbc.E08-03-0309
[56] Sukseree, S., Mildner, M., Rossiter, H., Pammer, J., Zhang, C.F., Watanapokasin, R., Tschachler, E., and Eckhart, L. (2012). Autophagy in the thymic epithelium is dispensable for the development of self-tolerance in a novel mouse model. PLoS One 7, e38933.10.1371/journal.pone.0038933
[57] Suzuki, K., and Ohsumi, Y. (2007). Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett 581, 2156-2161 .10.1016/j.febslet.2007.01.096
[58] Suzuki, T., Franchi, L., Toma, C., Ashida, H., Ogawa, M., Yoshikawa, Y., Mimuro, H., Inohara, N., Sasakawa, C., and Nunez, G. (2007). Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 3, e111.10.1371/journal.ppat.0030111
[59] Takeda, K., Kaisho, T., and Akira, S. (2003). Toll-like receptors. Annu Rev Immunol 21, 335-376 .10.1146/annurev.immunol.21.120601.141126
[60] Tanida, I., Ueno, T., and Kominami, E. (2004). LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36, 2503-2518 .10.1016/j.biocel.2004.05.009
[61] Tey, S.K., and Khanna, R. (2012). Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway. Blood 120, 994-1004 .10.1182/blood-2012-01-402404
[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., . (2010). Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11, 55-62 .10.1038/ni.1823
[63] Uhl, M., Kepp, O., Jusforgues-Saklani, H., Vicencio, J.M., Kroemer, G., and Albert, M.L. (2009). Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell death and differentiation 16, 991-1005 .10.1038/cdd.2009.8
[64] Weidberg, H., Shvets, E., and Elazar, Z. (2011). Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem 80, 125-156 .10.1146/annurev-biochem-052709-094552
[65] Willinger, T., and Flavell, R.A. (2012). 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 109, 8670-8675 .10.1073/pnas.1205305109
[66] Xu, Y., Jagannath, C., Liu, X.D., Sharafkhaneh, A., Kolodziejska, K.E., and Eissa, N.T. (2007). Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135-144 .10.1016/j.immuni.2007.05.022
[67] Yang, Z., and Klionsky, D.J. (2010). Eaten alive: a history of macroautophagy. Nat Cell Biol 12, 814-822 .10.1038/ncb0910-814
[68] Zhou, D., Li, P., Lin, Y., Lott, J.M., Hislop, A.D., Canaday, D.H., Brutkiewicz, R.R., and Blum, J.S. (2005). Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity 22, 571-581 .10.1016/j.immuni.2005.03.009