Search tips
Search criteria 


Logo of f1000bioLatest ContentReportsReportsReports
F1000 Biol Rep. 2010; 2: 61.
Published online 2010 August 19. doi:  10.3410/B2-61
PMCID: PMC2990412

Antigen processing for MHC presentation by autophagy


Autophagy delivers cytoplasmic constituents for lysosomal degradation. This catabolic pathway can be used to deliver intracellular antigens for major histocompatibility complex (MHC) class II presentation. In addition, recent evidence suggests that it also facilitates the processing of extracellular antigens for both MHC class I and II presentation.

Introduction and context

Classically, major histocompatibility complex (MHC) class I molecules present intracellular antigens to CD8+ T cells and MHC class II molecules present extracellular antigens to CD4+ T cells during adaptive immune responses. However, professional antigen-presenting cells, such as dendritic cells (DCs), can process extracellular antigen for MHC class I presentation by a pathway called cross-presentation [1]. Vice versa, fragments of nuclear and cytosolic antigens have been found among natural MHC class II ligands [2,3], and it has been shown that some antigens can be presented by MHC class II after intracellular processing [4,5]. Some of these use autophagy to gain access to lysosomal degradation in MHC class II loading compartments [6-10].

Primarily, one particular autophagic pathway, called macroautophagy, has been implicated in intracellular antigen processing for MHC class II presentation to CD4+ T cells. During macroautophagy an isolation membrane, which is thought to have originated from rough endoplasmic reticulum, the outer nuclear envelope membrane or the outer mitochondrial membrane [11-15], engulfs cytoplasmic constituents such as damaged organelles, protein aggregates and pathogens. Two ubiquitin-like systems with the Atg8 and Atg12 proteins at their heart are involved in extension of the autophagosomal membrane and substrate recruitment to its interior [16-18]. Upon completion of the resulting double membrane-surrounded autophagosome, these proteins are removed from the outer autophagosomal membrane, which then allows the fusion with lysosomes and late endosomes, such as multivesicular bodies (MVBs). The inner autophagosomal membrane and the autophagosome cargo are then broken down by lysosomal hydrolases. A subset of MVBs, known as MHC class II loading compartments, is used for antigen loading of MHC class II molecules. Autophagosomes fuse quite efficiently with these vesicles, resulting in MHC class II presentation of the autophagic cargo [19]. Thus, macroautophagy can deliver cytoplasmic antigens for MHC class II presentation to CD4+ T cells.

Major recent advances

In addition to the mechanistically fairly plausible intracellular antigen processing onto MHC class II molecules via macroautophagy, recent studies have also suggested that macroautophagy might assist with extracellular antigen processing for MHC class I and class II presentation. With respect to cross-presentation, two studies have demonstrated that viral and tumor antigens are more efficiently presented in trans to CD8+ T cells when the antigen donor cell can perform macroautophagy [20,21]. In the first of these studies, apoptosis-deficient mouse embryonic fibroblasts (Bax/Bak-/- MEFs) were more efficiently cross-presented after influenza A virus infection than wild-type MEFs. This cross-presentation was inhibited by small interfering RNA (siRNA)-mediated silencing of the essential macroautophagy gene product Atg5 [20]. In a second study, cross-presentation of the model antigen ovalbumin and the melanocyte differentiation antigen gp100 was diminished when macroautophagy was compromised in the antigen-donating epithelial and melanoma cell lines via siRNA knockdown of Atg6 and Atg12 [21]. These studies suggest that macroautophagy assists in the packaging of antigens for efficient cross-presentation.

In addition, macroautophagy seems to also facilitate the transport of endocytosed antigen to lysosomes for degradation as well as facilitating their loading onto MHC class II molecules. Enhanced delivery of phacocytosed material to lysosomes with the assistance of the molecular macroautophagy machinery was first described after Toll-like receptor 2 (TLR 2) stimulation of murine macrophages [22]. Furthermore, NOD2 stimulation enhanced macroautophagy, which enhanced lysosomal degradation of Salmonella [23]. This pathway also delivered Salmonella-encoded antigens for MHC class II presentation and was sensitive to siRNA-mediated silencing of Atg5, Atg7 and Atg16L1. Interestingly, mutations in NOD2 and Atg16L1, which predispose for Crohn's disease, also compromise both bacterial clearance and MHC class II presentation of bacterial antigens to CD4+ T cells. Along the same lines, Atg5-deficient DCs are compromised in priming CD4+ T cell responses after herpes simplex virus infection and in efficiently processing extracellular ovalbumin for MHC class II presentation [24]. At the same time, priming of CD8+ T cell responses and cross-presentation on MHC class I are not affected. Finally, HIV infection of DCs seems to inhibit macroautophagy in order to increase virus production and to prevent viral antigen presentation to CD4+ T cells [25]. Macroautophagy stimulation enhances, whereas siRNA-mediated silencing of Atg5 and Atg8 decreases, HIV antigen presentation on MHC class II but not on MHC class I molecules. Altogether, these data suggest that macroautophagy facilitates endosome cargo delivery for lysosomal degradation, which results in increased extracellular antigen processing for MHC class II presentation to CD4+ T cells.

Figure 1.
Macroautophagy regulates cross-presentation and intracellular as well as extracellular antigen presentation on major histocompatibility complex (MHC) class II molecules

Future directions

In light of these recent advances, it has become clear that macroautophagy regulates antigen presentation by MHC molecules beyond just intracellular antigen processing for CD4+ T cell stimulation. However, the mechanisms of antigen packaging by macroautophagy for cross-presentation and macroautophagy-mediated acceleration of endosome degradation by lysosomes remain elusive. In antigen donor cells, macroautophagy could provide the necessary energy to decorate dying cells with ligands for phagocytosis, such as, for example, phosphatidylserine, which needs to be flipped from the inner to the outer cell membrane leaflet in order to become an ‘eat-me’ signal [26,27]. Alternatively, autophagosome cargo could also be more efficiently released from MVBs via an alternative secretion pathway recently reported for the yeast Pichia pastoris and the slime mold Dictyostelium discoideum [28,29]. With respect to macroautophagic assistance for endosome fusion with lysosomes, it first needs to be clarified whether this represents an alternative use of Atgs, independent of macroautophagy, as was initially proposed [22], or whether amphisomes, the fusion vesicles between autophagosomes and endosomes, get targeted more rapidly to lysosomes. In a second step, the molecular basis for this enhanced targeting then needs to be elucidated. Irrespective of the mechanism, macroautophagic support for endosome fusion with lysosomes could explain why TLR coating increases antigen processing for MHC class II presentation [30]. Although much more needs to be done to characterize the underlying mechanisms, the recent studies discussed in this report suggest novel and exciting pathways in immunology, and cell biology in general, by which macroautophagy regulates endocytosis and exocytosis, in addition to its classical function in the degradation of cytoplasmic constituents by lysosomes.


Research in the author's laboratory is supported by the National Cancer Institute of the National Institutes of Health (R01CA108609 and R01CA101741), the Foundation for the National Institutes of Health (Grand Challenges in Global Health) and the Swiss National Science Foundation (310030_126995).


autophagy related gene
dendritic cell
mouse embryonic fibroblast
major histocompatibility complex
multivesicular body
small interfering RNA
Toll-like receptor


The electronic version of this article is the complete one and can be found at:


Competing Interests

The author declares that he has no competing interests.


1. Amigorena S, Savina A. Intracellular mechanisms of antigen cross presentation in dendritic cells. Curr Opin Immunol. 2010;22:109–17. doi: 10.1016/j.coi.2010.01.022. [PubMed] [Cross Ref]
2. Marrack P, Ignatowicz L, Kappler JW, Boymel J, Freed JH. Comparison of peptides bound to spleen and thymus class II. J Exp Med. 1993;178:2173–83. doi: 10.1084/jem.178.6.2173. [PMC free article] [PubMed] [Cross Ref]
3. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Müller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG, Stevanovic S. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A. 2005;102:7922–7. doi: 10.1073/pnas.0501190102. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Peter Van Endert 23 Jun 2005
4. Jaraquemada D, Marti M, Long EO. An endogenous processing pathway in vaccinia virus-infected cells for presentation of cytoplasmic antigens to class II-restricted T cells. J Exp Med. 1990;172:947–54. doi: 10.1084/jem.172.3.947. [PMC free article] [PubMed] [Cross Ref]
5. Münz C, Bickham KL, Subklewe M, Tsang ML, Chahroudi A, Kurilla MG, Zhang D, O'Donnell M, Steinman RM. Human CD4+ T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J Exp Med. 2000;191:1649–60. doi: 10.1084/jem.191.10.1649. [PMC free article] [PubMed] [Cross Ref]
6. Brazil MI, Weiss S, Stockinger B. Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules. Eur J Immunol. 1997;27:1506–14. doi: 10.1002/eji.1830270629. [PubMed] [Cross Ref]
7. Nimmerjahn F, Milosevic S, Behrends U, Jaffee EM, Pardoll DM, Bornkamm GW, Mautner J. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur J Immunol. 2003;33:1250–9. doi: 10.1002/eji.200323730. [PubMed] [Cross Ref]
8. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Münz C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science. 2005;307:593–6. doi: 10.1126/science.1104904. [PubMed] [Cross Ref] F1000 Factor 4.8 Must Read
Evaluated by Jonathan Howard 22 Feb 2005, Daniel Klionsky 01 Mar 2005
9. Dorfel D, Appel S, Grunebach F, Weck MM, Muller MR, 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;105:3199–205. doi: 10.1182/blood-2004-09-3556. [PubMed] [Cross Ref]
10. Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Jr, Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15:267–76. doi: 10.1038/nm.1928. [PubMed] [Cross Ref] F1000 Factor 8.1 Exceptional
Evaluated by Vojo Deretic 04 Mar 2009, Thomas W von Geldern 24 Mar 2009, George Yap 09 Apr 2009
11. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2009;11:1433–7. doi: 10.1038/ncb1991. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Michel Desjardins 23 Dec 2009
12. Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy. 2009;5:1180–5. doi: 10.4161/auto.5.8.10274. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Daniel Klionsky 01 Dec 2009
13. English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, Alexander D, Leib D, Norbury C, Lippe R, Desjardins M. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol. 2009;10:480–7. doi: 10.1038/ni.1720. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by George Yap 09 Apr 2009
14. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141:656–67. doi: 10.1016/j.cell.2010.04.009. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 4.8 Must Read
Evaluated by Ze'ev Ronai 01 Jun 2010, Yanzhuang Wang 01 Jul 2010
15. He C, Song H, Yorimitsu T, Monastyrska I, Yen WL, Legakis JE, Klionsky DJ. Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast. J Cell Biol. 2006;175:925–35. doi: 10.1083/jcb.200606084. [PMC free article] [PubMed] [Cross Ref]
16. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93. doi: 10.1146/annurev-genet-102808-114910. [PMC free article] [PubMed] [Cross Ref]
17. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2001;2:211–6. doi: 10.1038/35056522. [PubMed] [Cross Ref]
18. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75. doi: 10.1038/nature06639. [PMC free article] [PubMed] [Cross Ref]
19. Schmid D, Pypaert M, Münz 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. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Vojo Deretic 09 Jan 2007
20. Uhl M, Kepp O, Jusforgues-Saklani H, Vicencio JM, Kroemer G, Albert ML. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ. 2009;16:991–1005. doi: 10.1038/cdd.2009.8. [PubMed] [Cross Ref]
21. Li Y, Wang LX, Yang G, Hao F, Urba WJ, Hu HM. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res. 2008;68:6889–95. doi: 10.1158/0008-5472.CAN-08-0161. [PMC free article] [PubMed] [Cross Ref]
22. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007;450:1253–7. doi: 10.1038/nature06421. [PubMed] [Cross Ref] F1000 Factor 6.7 Must Read
Evaluated by Sergio Grinstein 07 Jan 2008, George Yap 08 Jan 2008, Daniel Klionsky 26 Feb 2008, Ulrich Schaible 17 Apr 2008
23. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–7. doi: 10.1038/nm.2069. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Christian Müenz 11 Dec 2009
24. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity. 2010;32:227–39. doi: 10.1016/j.immuni.2009.12.006. [PMC free article] [PubMed] [Cross Ref]
25. Blanchet FP, Moris A, Nikolic DS, Lehmann M, Cardinaud S, Stalder R, Garcia E, Dinkins C, Leuba F, Wu L, Schwartz O, Deretic V, Piguet V. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity. 2010;32:654–69. doi: 10.1016/j.immuni.2010.04.011. [PMC free article] [PubMed] [Cross Ref]
26. Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, Gilpin C, Levine B. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell. 2007;128:931–46. doi: 10.1016/j.cell.2006.12.044. [PubMed] [Cross Ref] F1000 Factor 6.4 Must Read
Evaluated by Eric Baehrecke 21 Mar 2007, Christoph Borner 26 Apr 2007
27. Mellen MA, de la Rosa EJ, Boya P. The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepithelium. Cell Death Differ. 2008;15:1279–90. doi: 10.1038/cdd.2008.40. [PubMed] [Cross Ref]
28. Manjithaya R, Anjard C, Loomis WF, Subramani S. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol. 2010;188:537–46. doi: 10.1083/jcb.200911149. [PMC free article] [PubMed] [Cross Ref]
29. Duran JM, Anjard C, Stefan C, Loomis WF, Malhotra V. Unconventional secretion of Acb1 is mediated by autophagosomes. J Cell Biol. 2010;188:527–36. doi: 10.1083/jcb.200911154. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 4.8 Must Read
Evaluated by Daniel Klionsky 02 Mar 2010, Kiyoshi Takeda 03 Mar 2010, John Kyriakis 10 Mar 2010, Brad Marsh 14 Apr 2010
30. Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006;440:808–12. doi: 10.1038/nature04596. [PubMed] [Cross Ref] F1000 Factor 11.6 Exceptional
Evaluated by Christopher Karp 06 Mar 2006, Torben Lund 10 Mar 2006, Peter Van Endert 10 Mar 2006, Elizabeth Mellins 29 Mar 2006, David Branch Moody 29 Mar 2006, Dan Conrad 13 Apr 2006, Laurence Eisenlohr 24 Apr 2006, Etienne Joly 27 Apr 2006, Marcus Thelen 17 May 2006, Victor Nizet 13 Jun 2006

Articles from F1000 Biology Reports are provided here courtesy of Faculty of 1000 Ltd