Abstract
MHC class II molecules are thought to present peptides derived from extracellular proteins to CD4+ T cells, which are important mediators of adaptive immunity to infections. In contrast, autophagy delivers constitutively cytosolic material for lysosomal degradation and has so far been recognized as an efficient mechanism of innate immunity against bacteria and viruses. Recent studies, however, link these two pathways and suggest that intracellular cytosolic and nuclear antigens are processed for MHC class II presentation after autophagy.
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Introduction
The T cells of the adaptive immune system monitor all body cells for the presence of pathogenic constituents with an elaborate detection system, involving display of microbial fragments on major histocompatibility complex (MHC) molecules at the cell surface. Proteins derived from intracellular or internalized pathogens are degraded by intracellular proteases into small protein fragments or peptides, which subsequently are loaded into the peptide-binding groove of MHC molecules. Peptide–MHC complexes are then presented on the cell surface and recognized by T cells with their specific T-cell receptor (TCR). There are two main classes of classical and polymorphic MHC molecules, MHC class I and II, that present peptides to two classes of T cells with different effector functions.1 MHC class I molecules present peptides to cytolytic CD8+ T cells and MHC class II molecules present peptides to CD4+ T cells, which can have both immunoregulatory and cytolytic functions. Protein fragments for MHC class I and II presentation are in their majority generated by distinct and different proteolytic events. MHC class I ligands are primarily produced by the proteasome, whereas MHC class II ligands are generated in lysosomes.2, 3 In this review, we will discuss the classical paradigm concerning the antigen processing for MHC class I and II presentation and will describe recent developments suggesting that autophagy contributes to the processing and presentation of intracellular antigens on MHC class II molecules.
The Paradigm of Antigen Processing for MHC Presentation
The two main classes of classical and polymorphic MHC molecules are loaded with protein fragments in distinct cellular compartments and their peptide cargo reaches these compartments by different routes: Antigens for MHC class I presentation are primarily degraded by the proteasome, a large multicatalytic protease complex residing in nucleus and cytosol.4 Targeting of these antigens for proteasomal degradation is often mediated by ubiquitinylation.5 A large proportion of MHC class I ligands is derived from the so-called defective ribosomal products (DRiPs),6, 7 which are degraded by the ubiquitin–proteasome system immediately after misfolding or premature termination of translation8 and provide cells with a rapid warning system against newly synthesized microbial proteins. The peptides generated by the proteasome are imported via the transporter associated with antigen processing (TAP) into the endoplasmic reticulum (ER),9 where they meet newly synthesized MHC class I molecules that have been cotranslationally inserted into the ER. With the help of the MHC class I loading complex, which includes chaperones, aminopeptidases and thiol oxidoreductases.10, 11, 12 individual peptides of 8–9 amino acids in length are loaded into the peptide-binding groove of MHC class I molecules. Stable peptide–MHC class I complexes are then exported via the Golgi apparatus to the cell surface for recognition by CD8+ T cells. Since MHC class I ligands are mainly generated in this proteasome- and TAP-dependent fashion, MHC class I antigens are thought to be primarily of cytosolic and nuclear origin.
In contrast, MHC class II ligands are thought to originate mainly from extracellular antigens, which are endocytosed by constitutively MHC class II-positive professional antigen-presenting cells (APCs) for presentation to the immune system. These endocytosed antigens are degraded by lysosomal endo- and exoproteases and meet MHC class II molecules in the so-called MHC class II compartments (MIICs) or class II vesicles (CIIV).13 MHC class II molecules migrate to these late endosomal compartments after cotranslational insertion into the ER, because they associate with the transmembrane protein invariant chain (Ii). Ii not only blocks the peptide-binding groove of newly synthesized MHC class II molecules,14 but also contains an endosomal targeting signal15 and thus targets MHC class II molecules to late endosomes, where they meet peptides generated by lysosomal proteases. In this MHC class II loading compartment, lysosomal proteases also degrade the Ii, and the remaining peptide (CLIP for class II-associated Ii peptide) is exchanged for antigenic peptides with the help of the nonclassical MHC class II molecule HLA-DM.16 As a result of this pathway, MHC class II ligands are generated from extracellular antigens after endocytosis and degradation in lysosomes. Hence, MHC class II antigens are thought to be primarily of extracellular origin.
Nonclassical Pathways of Antigen Presentation
Until recently, MHC class I and II molecules were thought to be specialized in presenting peptides derived from distinct sources. MHC class I ligands were thought to be derived from cytosolic and nuclear proteins, whereas MHC class II ligands were believed to be solely generated from extracellular sources. Although these classical pathways of antigen presentation remain correct, it has become apparent that other pathways contribute to antigen presentation and that antigens from inside and outside the cell can be presented on both MHC class I and II.17
The classical paradigm of antigen processing was first challenged, when it was discovered that professional APCs, especially dendritic cells (DCs), are able to present extracellular antigen not only on MHC class II, but also on MHC class I.18, 19 This new exogenous pathway, termed ‘crosspresentation’ pathway, is thought to be important in both immunity and tolerance. It allows DCs to prime CD8+ T-cell responses to antigens synthesized by cells other than DCs and to trigger both CD8+ and CD4+ T-cell responses at the same time, generating more effective and sustained T-cell responses.
The argument that the immune system should be able to survey all cell types and that antigens from all cellular compartments should be presented on both classes of MHC molecules, implies that a similar change in the antigen presentation paradigm might be necessary for MHC class II. Pathogens that replicate in the cytoplasm of professional APCs should be detectable for the immune system via both MHC class I and II presentation. Indeed, it has been shown that MHC class II molecules can present intracellular antigens, including cytosolic and nuclear proteins. This nonclassical MHC class II pathway was coined ‘endogenous MHC class II pathway’ and will be further discussed in the next paragraphs.
Endogenous MHC Class II Processing
The first evidence for the existence of an endogenous MHC class II pathway came from the analysis of natural MHC class II ligands. When MHC class II molecules were purified, primarily from Epstein–Barr virus (EBV)-transformed B lymphoblastoid cell lines (LCL), the majority of natural MHC class II ligands were found to be derived from intracellular proteins.20, 21 Surprisingly, more than 20% of the identified sequences came from cytosolic proteins21, 22 (Table 1). The sources of these peptides included cytoskeletal proteins (e.g. actin, tubulin, F-actin capping protein), constitutive metabolic enzymes (e.g. glyceraldehyde-3-phophate dehydrogenase (GAPDH), aspartate aminotransferase (AAT)), heat shock proteins (Hsp70)) and proteins involved in vesicular trafficking (Rab5A). In addition, a few of the identified peptides were derived from nuclear proteins, such as histones23 (Table 1).
Further evidence for the existence of an endogenous MHC class II pathway came from the fact that CD4+ T cell could recognize cytosolic and nuclear proteins after endogenous processing (Table 2). This pathway for CD4+ T-cell recognition was first described by Long and colleagues, who studied presentation of cytosolic measles virus and influenza virus antigens to CD4+ T cells.24, 25, 26, 27 These authors performed cell-mixing experiments to test whether the recognized antigens exit the cell and re-enter via endocytosis, that is, follow the classical MHC class II pathway. They observed, however, that antigen-specific CD4+ T cells did not recognize mixtures of antigen-negative, HLA class II-matched B cells with antigen-expressing, HLA class II-mismatched B cells, but only antigen-expressing, HLA class II-matched B cells, thereby demonstrating that the antigen was not released and then endocytosed for MHC class II presentation.24, 25 These experiments showed for the first time that endogenous processing of cytosolic antigens could lead to MHC class II presentation.
Subsequently, presentation of endogenous proteins on MHC class II has been described for a number of other viral antigens28, 29, 30, 31 as well as self-antigens,21, 32, 33, 34 model antigens,35, 36, 37, 38, 39, 40 and tumor antigens41, 42 (Table 2). On the basis of these findings, four endogenous MHC class II processing pathways can be postulated43, 44, 45 (Figure 1). Firstly, secreted/transmembrane proteins (e.g. influenza hemagglutinin (HA)28) can associate with newly synthesized MHC class II molecules in the ER, and then follow MHC class II–Ii complexes to endosomal compartments, where processing and peptide loading occurs. This pathway contributes the majority of endogenous MHC class II ligands, which were found to be derived from secreted/transmembrane proteins that intersect with the endocytic pathway.21, 22, 23 Secondly, cytosolic peptides can be imported into the ER via TAP for binding to MHC class II molecules.25 In certain APCs like DCs, this pathway is even accessed by exogenous antigens like influenza HA and neuraminidase, which leave the endosome for proteasome- and TAP-dependent processing onto MHC class II.46 A third pathway involves processing of cytosolic or nuclear proteins (e.g. glutamate decarboxylase 65 (GAD65)33) by the proteasome and is TAP independent.33, 40 For this pathway, peptides seem to be imported directly into endosomal/lysosomal compartments, via a transporter that was recently suggested to be Lamp-2a, the transporter of chaperone-mediated autophagy.47 In addition to these proteasome-dependent pathways, cytosolic and nuclear proteins can also be processed by a proteasome- and TAP-independent pathway: This fourth pathway involves the direct import of cytosolic/nuclear proteins (e.g. the EBV nuclear antigen 1 (EBNA1)30, 31) into endosomes/lysosomes and is in part mediated by autophagy. The latter three pathways (processing of cytosolic or nuclear proteins by proteasome-dependent or -independent mechanisms) contribute more than 20% of endogenous MHC class II ligands.21, 22, 23 Therefore, proteins residing in a compartment that is topologically distinct from the endocytic route and thus isolated from the classical MHC class II pathway, can gain access to MHC class II molecules and broaden the repertoire of MHC class II ligands.
Proteasome- and TAP-Independent Processing of Cytosolic and Nuclear Proteins
TAP- and proteasome-independent antigen processing of cytosolic and nuclear proteins onto MHC class II has been described for Influenza A matrix protein 1 (M1),27, 48 neomycin phosphotransferase II35 and the nuclear antigen 1 of the Epstein–Barr virus (EBNA1).31 Lysosomal proteases were shown to be responsible for antigen processing onto MHC class II in all three cases. For neomycin phosphotransferase II and EBNA1, autophagy was implicated in the delivery of antigens into lysosomes, while this has not been demonstrated for influenza matrix protein M1. However, when the half-life of M1 was modified with the N-end rule, only long-lived M1 (t1/2=5 h) was presented on MHC class II and able to stimulate CD4+ T cells, while short-lived M1 (t1/2=10 min) failed to be detected by M1-specific CD4+ T cells, but stimulated M1-specific CD8+ T cells.48 Autophagic protein degradation in lysosomes has been suggested to mainly discard long-lived proteins (t1/2>0.5 h),49 whereas many short-lived substrates are degraded by the proteasome.5, 50 Therefore, both long-lived M1 and EBNA1 (t1/2>20 h in B cells)51, 52, 53 fit the long half-life criteria of autophagy substrates. In addition, the long-lived cytosolic proteins GAPDH (t1/2=130 h)54 and Hsc70 (t1/2=20 h)55 were frequently identified as a source of natural MHC class II, but not class I ligands (Table 1).20 Hence, autophagic degradation might deliver long-lived endogenous proteins into the MHC class II pathway.
Delivery of Antigens to Lysosomes for MHC Class II Processing Via Autophagy
Involvement of autophagy in endogenous MHC class II processing has been demonstrated for only a few antigens. Neomycin phosphotransferase II,35 complement C532 and MUC142 were found to be processed onto MHC class II via autophagy after transfection. All these studies employed the pharmacologic inhibitors of autophagy, wortmannin56 and 3-methyladenine57 to inhibit CD4+ T-cell recognition of these antigens, but did not report any localization of the respective antigens to autophagosomes upon inhibition of lysosomal degradation. To date EBNA1 is the only pathogen-derived antigen for which processing onto MHC class II after autophagy has been demonstrated.31 We could visualize EBNA1-containing autophagosomes after inhibition of lysosomal degradation by fluorescence and electron microcopy. Furthermore, MHC class II-restricted EBNA1 recognition by CD4+ T cells was inhibited after RNA silencing of the essential autophagy gene atg1258 as well as after 3-methyladenine treatment. Autophagic delivery of EBNA1 for MHC class II processing was demonstrated in B-cell lines, which either were transfected with EBNA1 or expressed physiological levels of EBNA1 after B-cell transformation by EBV. These studies suggest that there might be a substantial overlap between the autophagic route of degradation and MHC class II loading. This implies that autophagic destruction of other pathogens like Mycobacterium tuberculosis59 and Streptococcus pyogenes60 might also result in MHC class II presentation of antigens from these pathogens. Since IFNγ has been shown to upregulate autophagy,59 activated CD4+ T cells might then even further stimulate infected cells in order to clear intracellular pathogens. Therefore, autophagy might mediate innate resistance to pathogens, lead to MHC class II presentation of pathogenic determinants and be used as effector mechanism of adaptive immunity to target intracellular pathogens.
Further evidence for the involvement of autophagy in antigen processing for MHC class II presentation comes from biochemical studies on natural HLA-DR ligands.61 In this study, the authors characterized peptides, which were eluted from immunoaffinity-purified HLA-DR molecules of an EBV-transformed B LCL. The MHC class II ligandomes of LCLs in the steady state and after induction of autophagy via starvation were compared. After 24 h of starvation the MHC class II presentation of peptides from intracellular and lysosomal proteins rose by more than 50%, while presentation of membrane and secreted proteins remained constant. The four most regulated MHC class II ligands were derived from one lysosomal (cathepsin D) and three cytosolic/nuclear proteins (eukaryotic translation elongation factor 1 alpha, ubiquitin-protein ligase NEDD4La and RAD23 homolog B nucleotide excision repair protein). In the same study, the extensive analysis of HLA-DR ligands from LCLs cultured in nutrient-rich conditions revealed a peptide, derived from the essential autophagy gene product Atg8/LC3. Atg8/LC3, which is coupled to the autophagosome membrane in an ubiquitin-like fashion, is essential for autophagosome formation.62 These findings suggest that upregulation of autophagy leads to enhanced MHC class II presentation of cytosolic/nuclear proteins and that autophagosomes constitutively fuse with MHC class II-loading compartments.
Transport of Autophagosomes to MHC Class II Loading Compartments
It is well established that MHC class II molecules localize to endosomal compartments, where they meet processed antigen and get loaded with antigenic peptide. The nature of this MHC class II-loading compartment (termed ‘MIIC’ for MHC class II compartment) has been studied extensively using immunofluorescence or electron microscopy and cell fractionation.13, 63, 64 These studies have characterized MIICs as late endosomal compartments containing the late endosomal/lysosomal markers LAMP1, CD63 and partially processed cathepsin D. Since no late endosomes/lysosomes devoid of MHC class II and HLA-DM are observed in MHC class II-expressing APCs, it is thought that MHC class II-loading compartments are conventional endosomal compartments that, in addition, contain the components for MHC class II loading, namely MHC class II and the peptide-loading chaperone HLA-DM.13, 65, 66 This implies that classical APCs like macrophages, B cells and DCs have equipped late endosomes for MHC class II loading.
In electron microscopy, MIIC compartments have a typical multivesicular or multilaminar morphology.65, 66, 67, 68 The multivesicular phenotype can be explained by the transport of MHC class II molecules to multivesicular endosomes, which are abundant in the endocytic pathway.69 The multilaminar, ‘onion-like’ phenotype of MIICs, however, has remained more enigmatic. It is tempting to speculated that MIICs obtain their multilaminar phenotype by fusion of MHC class II-containing endosomes with autophagosomes, given the fact that autophagosomes are delineated by a double membrane and often contain internal membrane sheets.70, 71 Indeed, electron microscopy studies have demonstrated that the endocytic pathway converges with the autophagy pathway: Endosomal compartments, labeled with colloidal gold as an endocytic tracer, were found to fuse with double-membrane bound, gold-negative autophagosomes to form endosome–autophagosome fusion compartments called ‘amphisomes’.72, 73 Amphisomes contained both endocytosed gold and undegraded cytoplasm and were delimited by double or multiple membranes.73 Often, fusion compartments also contained multiple internal vesicles, presumably due to the fusion of autophagosomes with multivesicular endosomes. Hence, autophagosomes fuse with different types of endosomal compartments and thus deliver autophagy substrates into the endocytic route. In MHC class II-expressing cells, this fusion event could constitutively lead to the delivery of autophagy substrates into endosomal MIIC compartments and thus loading of processed autophagy substrates onto MHC class II molecules (Figure 2).
Possible Role for MHC Class II Processing Via Autophagy During the Development of the Immune System and during Adaptive Immune Responses
So far MHC class II presentation after autophagy has only been described in classical APCs like macrophages,32 B cells31, 35 and DCs.42 However, endogenous MHC class II processing might be much more relevant for MHC class II-positive tissues with little or no phagocytic capacity. Along these lines, murine cortical epithelial cells of the thymus were found to have high constitutive autophagy, especially in newborn mice.74 These cells are believed to have low phagocytic potential, but are nevertheless involved in positive selection of CD4+ T cells.75 This implies that the MHC class II complexes involved in positive CD4+ T-cell selection have to be loaded from endogenous sources, and high constitutive autophagy might deliver some of the necessary antigens into MHC class II-loading compartments.
Thymic epithelium is not the only somatic tissue with MHC class II presentation. Upon immune activation and inflammation, endothelial and epithelial cells as well as nearly all lymphocytes can upregulate HLA class II,76 while phagocytosis is not enhanced. This suggests that MHC class II molecules on inflamed tissues might display primarily endogenous ligands for immune surveillance by CD4+ T cells. The induction of CD4+ T cells alongside with CD8+ T cells is an important prerequisite for an effective adaptive immune response, since the development77, 78, 79 and maintenance80, 81, 82, 83, 84 of CD8+ memory T cells is dependent on help from CD4+ T cells. Additionally, CD4+ T cells can have direct cytotoxic effects on virus-infected cells85, 86, 87, 88 and contribute to the control of viral infections.89, 90, 91, 92, 93 Given these important roles of CD4+ T cells for adaptive immunity, it seems crucial that endogenous antigen be presented not only on MHC class I, but also on MHC class II. We suggest that part of these endogenous MHC class II ligands are generated from autophagy substrates and that MHC class II presentation of long-lived endogenous substrates complements MHC class I presentation of short-lived endogenous substrates to elicit T-cell activation during immune responses.
Conclusions
Autophagy is an innate defense mechanism against microbial pathogens.94, 95 Recent evidence suggests that autophagic degradation products are displayed on MHC class II for immune surveillance by CD4+ T cells. So far autophagy has been found to deliver nuclear and cytosolic proteins for MHC class II presentation in professional APCs, namely DCs, macrophages and B cells. Since, especially in DCs, endosomes seem to be leaky and release exogenous antigen for crosspresentation on MHC class I, it is also conceivable that autophagic delivery of endogenous antigen into late endosomes contributes to MHC class I loading after protein escape into the cytosol. Thus, autophagy may contribute to immune control of infected APCs, such as EBV-transformed B cells. However, we suggest that this pathway is also used for the immune surveillance of tissues that upregulate MHC class II upon inflammation as well as for positive T-cell selection by thymic epithelial cells.
Abbreviations
- MHC:
-
major histocompatibility complex
- TCR:
-
T-cell receptor
- DriPs:
-
defective ribosomal products
- TAP:
-
transporter associated with antigen processing
- APC:
-
antigen-presenting cell
- MIIC:
-
MHC class II compartment
- I i :
-
invariant chain
- HLA:
-
human leukocyte antigen
- DC:
-
dendritic cell
- EBV:
-
Epstein–Barr virus
- EBNA1:
-
EBV nuclear antigen 1
- LCL:
-
lymphoblastoid cell line
- M1:
-
influenza A matrix protein 1
- LAMP:
-
lysosome-associated membrane protein
References
Swain SL (1983) T cell subsets and the recognition of MHC class. Immunol. Rev. 74: 129–142
Pamer E and Cresswell P (1998) Mechanisms of MHC class I-restricted antigen processing. Annu. Rev. Immunol. 16: 323–358
Busch R and Mellins ED (1996) Developing and shedding inhibitions: how MHC class II molecules reach maturity. Curr. Opin. Immunol. 8: 51–58
Kloetzel PM (2004) Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nat. Immunol. 5: 661–669
Ciechanover A, Finley D and Varshavsky A (1984) Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell 37: 57–66
Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW and Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404: 770–774
Reits EA, Vos JC, Gromme M and Neefjes J (2000) The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404: 774–778
Yewdell JW, Reits E and Neefjes J (2003) Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat. Rev. Immunol. 3: 952–961
Momburg F and Hengel H (2002) Corking the bottleneck: the transporter associated with antigen processing as a target for immune subversion by viruses. Curr. Top. Microbiol. Immunol. 269: 57–74
Dick TB (2004) Assembly of MHC class I peptide complexes from the perspective of disulfide bond formation. Cell. Mol. Life Sci. 61: 547–556
Lehner PJ and Cresswell P (2004) Recent developments in MHC-class-I-mediated antigen presentation. Curr. Opin. Immunol. 16: 82–89
Shastri N, Schwab S and Serwold T (2002) Producing nature's gene-chips: the generation of peptides for display by MHC class I molecules. Annu. Rev. Immunol. 20: 463–493
Neefjes J (1999) CIIV, MIIC and other compartments for MHC class II loading. Eur. J. Immunol. 29: 1421–1425
Roche PA and Cresswell P (1990) Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature 345: 615–618
Odorizzi CG, Trowbridge IS, Xue L, Hopkins CR, Davis CD and Collawn JF (1994) Sorting signals in the MHC class II invariant chain cytoplasmic tail and transmembrane region determine trafficking to an endocytic processing compartment. J. Cell. Biol. 126: 317–330
Busch R, Doebele RC, Patil NS, Pashine A and Mellins ED (2000) Accessory molecules for MHC class II peptide loading. Curr. Opin. Immunol. 12: 99–106
Trombetta ES and Mellman I (2005) Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23: 975–1028
Bevan MJ (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
Heath WR and Carbone FR (2001) Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19: 47–64
Rammensee H, Bachmann J, Emmerich NP, Bachor OA and Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50: 213–219
Dongre AR, Kovats S, deRoos P, McCormack AL, Nakagawa T, Paharkova-Vatchkova V, Eng J, Caldwell H, Yates III JR and Rudensky AY (2001) In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31: 1485–1494
Chicz RM, Urban RG, Gorga JC, Vignali DA, Lane WS and Strominger JL (1993) Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J. Exp. Med. 178: 27–47
Friede T, Gnau V, Jung G, Keilholz W, Stevanovic S and Rammensee HG (1996) Natural ligand motifs of closely related HLA-DR4 molecules predict features of rheumatoid arthritis associated peptides. Biochim. Biophys. Acta 1316: 85–101
Jacobson S, Sekaly RP, Jacobson CL, McFarland HF and Long EO (1989) HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells. J. Virol. 63: 1756–1762
Malnati MS, Marti M, LaVaute T, Jaraquemada D, Biddison W, DeMars R and Long EO (1992) Processing pathways for presentation of cytosolic antigen to MHC class II-restricted T cells. Nature 357: 702–704
Nuchtern JG, Biddison WE and Klausner RD (1990) Class II MHC molecules can use the endogenous pathway of antigen presentation. Nature 343: 74–76
Jaraquemada D, Marti M and Long EO (1990) An endogenous processing pathway in vaccinia virus-infected cells for presentation of cytoplasmic antigens to class II-restricted T cells. J. Exp. Med. 172: 947–954
Aichinger G, Karlsson L, Jackson MR, Vestberg M, Vaughan JH, Teyton L, Lechler RI and Peterson PA (1997) Major histocompatibility complex class II-dependent unfolding, transport, and degradation of endogenous proteins. J. Biol. Chem. 272: 29127–29136
Chen M, Shirai M, Liu Z, Arichi T, Takahashi H and Nishioka M (1998) Efficient class II major histocompatibility complex presentation of endogenously synthesized hepatitis C virus core protein by Epstein–Barr virus-transformed B-lymphoblastoid cell lines to CD4+ T cells. J. Virol. 72: 8301–8308
Münz C, Bickham KL, Subklewe M, Tsang ML, Chahroudi A, Kurilla MG, Zhang D, O’Donnell M and Steinman RM (2000) Human CD4+ T lymphocytes consistently respond to the latent Epstein–Barr virus nuclear antigen EBNA1. J. Exp. Med. 191: 1649–1660
Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T and Münz C (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307: 593–596
Brazil MI, Weiss S and Stockinger B (1997) Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules. Eur. J. Immunol. 27: 1506–1514
Lich JD, Elliott JF and Blum JS (2000) Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. J. Exp. Med. 191: 1513–1524
Weiss S and Bogen B (1991) MHC class II-restricted presentation of intracellular antigen. Cell 64: 767–776
Nimmerjahn F, Milosevic S, Behrends U, Jaffee EM, Pardoll DM, Bornkamm GW and Mautner J (2003) Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33: 1250–1259
Qi L, Rojas JM and Ostrand-Rosenberg S (2000) Tumor cells present MHC class II-restricted nuclear and mitochondrial antigens and are the predominant antigen presenting cells in vivo. J. Immunol. 165: 5451–5461
Oukka M, Colucci-Guyon E, Tran PL, Cohen-Tannoudji M, Babinet C, Lotteau V and Kosmatopoulos K (1996) CD4T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity 4: 545–553
Bonifaz LC, Arzate S and Moreno J (1999) Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. Eur. J. Immunol. 29: 119–131
Mukherjee P, Dani A, Bhatia S, Singh N, Rudensky AY, George A, Bal V, Mayor S and Rath S (2001) Efficient presentation of both cytosolic and endogenous transmembrane protein antigens on MHC class II is dependent on cytoplasmic proteolysis. J. Immunol. 167: 2632–2641
Dani A, Chaudhry A, Mukherjee P, Rajagopal D, Bhatia S, George A, Bal V, Rath S and Mayor S (2004) The pathway for MHCII-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment. J. Cell. Sci. 117 (Part 18): 4219–4230
Wang RF, Wang X, Atwood AC, Topalian SL and Rosenberg SA (1999) Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. Science 284: 1351–1354
Dörfel D, Appel S, Grunebach F, Weck MM, Muller MR, 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
Lechler R, Aichinger G and Lightstone L (1996) The endogenous pathway of MHC class II antigen presentation. Immunol. Rev. 151: 51–79
Zhou D and Blum JS (2004) Presentation of cytosolic antigens via MHC class II molecules. Immunol. Res. 30: 279–290
Unanue ER (2002) Perspective on antigen processing and presentation. Immunol. Rev. 185: 86–102
Tewari MK, Sinnathamby G, Rajagopal D and Eisenlohr LC (2005) A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent. Nat. Immunol. 6: 287–294
Zhou D, Li P, Lott JM, Hislop A, Canaday DH, Brutkiewicz RR and Blum JS (2005) Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity 22: 571–581
Gueguen M and Long EO (1996) Presentation of a cytosolic antigen by major histocompatibility complex class II molecules requires a long-lived form of the antigen. Proc. Natl. Acad. Sci. USA 93: 14692–14697
Henell F, Berkenstam A, Ahlberg J and Glaumann H (1987) Degradation of short- and long-lived proteins in perfused liver and in isolated autophagic vacuoles – lysosomes. Exp. Mol. Pathol. 46: 1–14
Finley D, Ciechanover A and Varshavsky A (1984) Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. Cell 37: 43–55
Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A and Masucci MG (1997) Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein–Barr virus nuclear antigen 1. Proc. Natl. Acad. Sci. USA 94: 12616–12621
Tellam J, Connolly G, Green KJ, Miles JJ, Moss DJ, Burrows SR and Khanna R (2004) Endogenous presentation of CD8+ T cell epitopes from Epstein–Barr virus nuclear antigen 1. J. Exp. Med. 199: 1421–1431
Tellam J, Sherritt M, Thomson S, Tellam R, Moss DJ, Burrows SR, Wiertz E and Khanna R (2001) Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+ T cell recognition. J. Biol. Chem. 276: 33353–33360
Dice JF and Goldberg AL (1975) A statistical analysis of the relationship between degradative rates and molecular weights of proteins. Arch. Biochem. Biophys. 170: 213–219
Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J and Patterson C (2001) CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J. Biol. Chem. 276: 42938–42944
Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H and Meijer AJ (1997) The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243: 240–246
Seglen PO and Gordon PB (1982) 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad. Sci. USA 79: 1889–1892
Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M and Ohsumi Y (1998) A protein conjugation system essential for autophagy. Nature 395: 395–398
Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI and Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119: 753–766
Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S and Yoshimori T (2004) Autophagy defends cells against invading group A Streptococcus. Science 306: 1037–1040
Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG and Stevanovic S (2005) Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl. Acad. Sci. USA Published May 13, 2005, 10.1073/pnas.0501190102
Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat. Rev. Mol. Cell. Biol. 2: 211–216
Peters PJ, Neefjes JJ, Oorschot V, Ploegh HL and Geuze HJ (1991) Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments. Nature 349: 669–676
Tulp A, Verwoerd D, Dobberstein B, Ploegh HL and Pieters J (1994) Isolation and characterization of the intracellular MHC class II compartment. Nature 369: 120–126
Sanderson F, Kleijmeer MJ, Kelly A, Verwoerd D, Tulp A, Neefjes JJ, Geuze HJ and Trowsdale J (1994) Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science 266: 1566–1569
Kleijmeer MJ, Morkowski S, Griffith JM, Rudensky AY and Geuze HJ (1997) Major histocompatibility complex class II compartments in human and mouse B lymphoblasts represent conventional endocytic compartments. J. Cell. Biol. 139: 639–649
Calafat J, Nijenhuis M, Janssen H, Tulp A, Dusseljee S, Wubbolts R and Neefjes J (1994) Major histocompatibility complex class II molecules induce the formation of endocytic MIIC-like structures. J. Cell. Biol. 126: 967–977
Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J, Janssen H, Calafat J, van Ham M, Janssen L, van Lith M, Jalink K and Neefjes J (2005) Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape. Immunity 22: 221–233
Gruenberg J and Stenmark H (2004) The biogenesis of multivesicular endosomes. Nat. Rev. Mol. Cell. Biol. 5: 317–323
Ohsumi Y and Mizushima N (2004) Two ubiquitin-like conjugation systems essential for autophagy. Semin. Cell. Dev. Biol. 15: 231–236
Niemann A, Takatsuki A and Elsasser HP (2000) The lysosomotropic agent monodansylcadaverine also acts as a solvent polarity probe. J. Histochem. Cytochem. 48: 251–258
Liou W, Geuze HJ, Geelen MJ and Slot JW (1997) The autophagic and endocytic pathways converge at the nascent autophagic vacuoles. J. Cell. Biol. 136: 61–70
Berg TO, Fengsrud M, Stromhaug PE, Berg T and Seglen PO (1998) Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem. 273: 21883–21892
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
Starr TK, Jameson SC and Hogquist KA (2003) Positive and negative selection of T cells. Annu. Rev. Immunol. 21: 139–176
Reith W and Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19: 331–373
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF and Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393: 478–480
Ridge JP, Di Rosa F and Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T- helper and a T-killer cell. Nature 393: 474–478
Schoenberger SP, Toes RE, van der Voort EI, Offringa R and Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393: 480–483
Cardin RD, Brooks JW, Sarawar SR and Doherty PC (1996) Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184: 863–871
Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD and Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188: 2205–2213
Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL, Ghrayeb J, Murthy KK, Rice CM and Walker CM (2003) HCV persistence and immune evasion in the absence of memory T cell help. Science 302: 659–662
Shedlock DJ and Shen H (2003) Requirement for CD4T cell help in generating functional CD8T cell memory. Science 300: 337–339
Sun JC and Bevan MJ (2003) Defective CD8T cell memory following acute infection without CD4T cell help. Science 300: 339–342
Stalder T, Hahn S and Erb P (1994) Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J. Immunol. 152: 1127–1133
Hahn S, Gehri R and Erb P (1995) Mechanism and biological significance of CD4-mediated cytotoxicity. Immunol. Rev. 146: 57–79
Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, Easterbrook P, Grey P, Smith D, McMichael AJ, Cooper DA, Rowland-Jones SL and Kelleher AD (2002) Characterization of CD4+ CTLs ex vivo. J. Immunol. 168: 5954–5958
Jellison ER, Kim SK and Welsh RM (2005) Cutting edge: MHC class II-restricted killing in vivo during viral infection. J. Immunol. 174: 614–618
Paludan C, Bickham K, Nikiforow S, Tsang ML, Goodman K, Hanekom WA, Fonteneau JF, Stevanovic S and Münz C (2002) EBNA1 specific CD4+ Th1 cells kill Burkitt's lymphoma cells. J. Immunol. 169: 1593–1603
Nikiforow S, Bottomly K, Miller G and Münz C (2003) Cytolytic CD4+-T-cell clones reactive to EBNA1 inhibit Epstein–Barr virus-induced B-cell proliferation. J. Virol. 77: 12088–12104
Stevenson PG, Cardin RD, Christensen JP and Doherty PC (1999) Immunological control of a murine gammaherpesvirus independent of CD8+ T cells. J. Gen. Virol. 80 (Part 2): 477–483
Sparks-Thissen RL, Braaten DC, Kreher S, Speck SH and Virgin HW (2004) An optimized CD4 T-cell response can control productive and latent gamma herpesvirus infection. J. Virol. 78: 6827–6835
Robertson KA, Usherwood EJ and Nash AA (2001) Regression of a murine gamma herpesvirus 68-positive B-cell lymphoma mediated by CD4T lymphocytes. J. Virol. 75: 3480–3482
Shintani T and Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306: 990–995
Levine B (2005) Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120: 159–162
Münz C, Hofmann M, Yoshida K, Moustakas AK, Kikutani H, Stevanovic S, Papadopoulos GK and Rammensee HG (2002) Peptide analysis, stability studies, and structural modeling explain contradictory peptide motifs and unique properties of the NOD mouse MHC class II molecule H2-Ag7. Eur. J. Immunol. 32: 2105–2116
Muntasell A, Carrascal M, Alvarez I, Serradell L, van Veelen P, Verreck FA, Koning F, Abian J and Jaraquemada D (2004) Dissection of the HLA-DR4 peptide repertoire in endocrine epithelial cells: strong influence of invariant chain and HLA-DM expression on the nature of ligands. J. Immunol. 173: 1085–1093
Acknowledgements
We thank the National Cancer Institute (R01CA108609), the Leukemia and Lymphoma Society and the New York Academy of Medicine for supporting our research (to CM). DS is supported by a predoctoral fellowship from the Schering Foundation.
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Schmid, D., Münz, C. Immune surveillance of intracellular pathogens via autophagy. Cell Death Differ 12 (Suppl 2), 1519–1527 (2005). https://doi.org/10.1038/sj.cdd.4401727
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DOI: https://doi.org/10.1038/sj.cdd.4401727
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