Chapter 11 : Antigen Processing and Presentation Mechanisms in Myeloid Cells

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Major histocompatibility complex class I molecules (MHC-I) and class II molecules (MHC-II) are transmembrane glycoproteins that share the property of binding short peptides that are produced by the cells that express them. The generation of peptides and their subsequent association with MHC molecules is referred to as antigen processing. Antigen processing by myeloid cells, particularly dendritic cells (DCs), and the presentation of antigen-derived peptides to CD4 and CD8 T cells by MHC-I and MHC-II expressed on these cells are critical steps for effective adaptive immune responses. However, the mechanisms involved in antigen processing for MHC-I and MHC-II are different ( Fig. 1 ). For recognition by mature effector CD4 T cells MHC-II-associated peptides are generated and bind within the endolysosomal system, while for recognition by mature CD8 T cells MHC-I-associated peptides are generated in the cytosol from newly synthesized proteins and bind to MHC-I molecules in the endoplasmic reticulum (ER). For priming naive CD4 T cells, the MHC-II processing pathway used by DCs also relies on peptide generation and binding in the endolysosomal system. However, priming CD8 T cells requires endocytosis of antigens by the DCs followed by their transfer into the cytosol for proteolysis into peptides that ultimately bind to MHC-I molecules, a process known as cross-presentation or cross-priming. In this chapter we will discuss both general and myeloid-specific mechanisms of both MHC-I- and MHC-II-restricted antigen processing and presentation, phenomena that are intimately involved with the biosynthesis of the MHC glycoproteins.

Citation: Roche P, Cresswell P. 2017. Antigen Processing and Presentation Mechanisms in Myeloid Cells, p 209-223. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0008-2015
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Figure 1

Overview of MHC-peptide complex biogenesis. Cytosolic proteins are degraded by the proteasome into small peptides that are imported into the lumen of the ER by TAP, where they bind to nascent MHC-I molecules. ER peptides can be trimmed to 8 to 10 residues by the action of ERAAP/ERAP1 and ERAP2. Fully assembled MHC-I–peptide complexes leave the ER and are delivered to the plasma membrane by recognition by CD8 T cells. Proteins internalized into endosomes by a variety of mechanisms are degraded into peptides in late endosomes rich in proteinases, classically called cathepsins, active at acidic pH. MHC-II molecules are transported to these compartments from the ER by virtue of its association with a chaperone termed the invariant chain (not shown). The MHC-II-positive compartment is indicated as MIIC/late endosome in the figure. Invariant chain is also proteolytically degraded in late endosomes, thereby making the MHC-II molecules available for peptide binding. Following a series of peptide-editing processes, immunodominant MHC-II–peptide complexes move to the plasma membrane for recognition by CD4 T cells. In specialized APCs, particularly DCs, proteins that enter the cell by endocytosis/phagocytosis are retrotranslocated into the cytosol for subsequent proteasomal degradation and binding to MHC-I in a process termed cross-presentation. The retrotranslocation mechanism is currently undefined, but here it is depicted as a channel responsible for ERAD that may be recruited to the phagosome from the ER. This hypothesis remains unproven. Reprinted from reference , with permission.

Citation: Roche P, Cresswell P. 2017. Antigen Processing and Presentation Mechanisms in Myeloid Cells, p 209-223. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0008-2015
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Figure 2

Biosynthesis of MHC-II–peptide complexes. MHC-II αβ dimers associate with I in the ER, and the assembled MHC-II–I complexes traffic through the Golgi apparatus and are delivered to the plasma membrane. The complexes are internalized by clathrin-mediated endocytosis and are transported to late endosomal multivesicular antigen-processing compartments. Some of these complexes sort onto the ILVs of these compartments, where sequential I proteolysis leads to persistence of a derived fragment (termed CLIP) in the MHC-II peptide-binding groove. CLIP is removed from CLIP–MHC-II complexes by DM molecules that are present on the ILV and limiting membrane of antigen-processing compartments, thereby allowing peptide binding onto nascent MHC-II. The activity of DM is regulated by DO; however, the mechanism of regulation remains unknown. It is likely that ILV-associated MHC-II is transferred to the limiting membrane and endo/lysosomal tubules that either directly fuse, or give rise to transport vesicles that fuse, with the plasma membrane. MHC-II–peptide association with lipid microdomains first occurs in antigen-processing compartments and allows clustering of MHC-II–peptide complexes on the cell surface. If an entire antigen-processing compartment fuses with the plasma membrane, the ILV can be released from the cell in the form of exosomes. Surface-expressed MHC-II–peptide complexes can internalize using a clathrin-independent endocytosis pathway and are targeted for lysosomal degradation or may be recycled back to the plasma membrane. Reprinted from reference , with permission.

Citation: Roche P, Cresswell P. 2017. Antigen Processing and Presentation Mechanisms in Myeloid Cells, p 209-223. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0008-2015
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Figure 3

MHC-I biosynthesis and peptide binding. The proteasome generates short antigenic peptides capable of binding to MHC-I molecules. These peptides are derived from native cytosolic proteins, defective ribosomal products (DRiPs), or, in the case of cross-presentation, exogenous proteins that enter the cell by phagocytosis and are translocated into the cytosol, either intact or as large proteolytic fragments. In cross-presenting mouse CD8 DCs, the presence of NOX2 on the phagosomal membrane neutralizes acidification and reduces proteolytic activity, preserving protein integrity. Nascent MHC-I heavy chains initially interact with the molecular chaperone calnexin (CNX) and, after binding βm, are recruited to the PLC by simultaneous noncovalent CRT interactions with a monoglucosylated N-linked glycan on the heavy chain and ERp57 disulfide linked to tapasin in the PLC. Peptide-free MHC-I molecules and those possessing suboptimal ligands are subject to a series of “editing” steps mediated by interaction with tapasin within the PLC as well as maintenance of the monoglucosylated N-linked glycan by the opposing actions of the enzymes glucosidase 2 (GlsII), which removes the terminal glucose residue, and UGT1, which adds back glucose to preserve the CRT interaction. MHC-I molecules containing high-affinity peptides ultimately leave the ER and are transported to the plasma membrane. Reprinted from reference , with permission.

Citation: Roche P, Cresswell P. 2017. Antigen Processing and Presentation Mechanisms in Myeloid Cells, p 209-223. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0008-2015
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Figure 4

Pathways of antigen entry into the processing compartments of myeloid cells. Pathogens as well as soluble and particulate antigens access the endolysosomal pathway of antigen-processing cells by a variety of mechanisms. Clathrin-mediated endocytosis generally involves the binding of ligands to one of a variety of endocytic receptors that deliver endocytosed cargo to early endosomes. Macropinocytosis is a nonspecific form of endocytosis that involves actin-dependent membrane ruffling that leads to solute encapsulation in structures that give rise to macropinosomes. Like early endosomes, macropinosomes are not highly proteolytic and antigen degradation only occurs following their fusion with acidic late endosomal/lysosomal compartments containing lysosomal proteinases. Pathogens and large particles that possess specific binding sites for surface receptors are internalized by phagocytosis, an endocytic process that combines the features of macropinocytosis and receptor-mediated endocytosis. Phagosomes are not acidic nor proteinase rich; however, maturation of phagosomes by fusion with late endosomes or lysosomes gives rise to proteolytic phagolysosomes that degrade phagocytosed material. Autophagy also provides material for endolysosomal degradation by sequestering cytosol into a double-membrane encapsulated autophagosome that, like a conventional phagosome, undergoes maturation upon fusion with lysosomes to generate proteolytic autophagolysosomes. Reprinted from reference , with permission.

Citation: Roche P, Cresswell P. 2017. Antigen Processing and Presentation Mechanisms in Myeloid Cells, p 209-223. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0008-2015
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1. Anderson MS,, Miller J . 1992. Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89 : 2282 2286.[PubMed] [CrossRef]
2. Elliott EA,, Drake JR,, Amigorena S,, Elsemore J,, Webster P,, Mellman I,, Flavell RA . 1994. The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules. J Exp Med 179 : 681 694.[PubMed] [CrossRef]
3. Roche PA,, Cresswell P . 1990. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature 345 : 615 618.[PubMed] [CrossRef]
4. Teyton L,, O’Sullivan D,, Dickson PW,, Lotteau V,, Sette A,, Fink P,, Peterson PA . 1990. Invariant chain distinguishes between the exogenous and endogenous antigen presentation pathways. Nature 348 : 39 44.[PubMed] [CrossRef]
5. Bakke O,, Dobberstein B . 1990. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell 63 : 707 716.[PubMed] [CrossRef]
6. Lotteau V,, Teyton L,, Peleraux A,, Nilsson T,, Karlsson L,, Schmid SL,, Quaranta V,, Peterson PA . 1990. Intracellular transport of class II MHC molecules directed by invariant chain. Nature 348 : 600 605.[PubMed] [CrossRef]
7. Hiltbold EM,, Roche PA . 2002. Trafficking of MHC class II molecules in the late secretory pathway. Curr Opin Immunol 14 : 30 35.[PubMed] [CrossRef]
8. Pieters J,, Bakke O,, Dobberstein B . 1993. The MHC class II-associated invariant chain contains two endosomal targeting signals within its cytoplasmic tail. J Cell Sci 106 : 831 846.[PubMed]
9. Dugast M,, Toussaint H,, Dousset C,, Benaroch P . 2005. AP2 clathrin adaptor complex, but not AP1, controls the access of the major histocompatibility complex (MHC) class II to endosomes. J Biol Chem 280 : 19656 19664.[PubMed] [CrossRef]
10. McCormick PJ,, Martina JA,, Bonifacino JS . 2005. Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments. Proc Natl Acad Sci U S A 102 : 7910 7915.[PubMed] [CrossRef]
11. Castellino F,, Germain RN . 1995. Extensive trafficking of MHC class II-invariant chain complexes in the endocytic pathway and appearance of peptide-loaded class II in multiple compartments. Immunity 2 : 73 88.[PubMed] [CrossRef]
12. Roche PA,, Teletski CL,, Stang E,, Bakke O,, Long EO . 1993. Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization. Proc Natl Acad Sci U S A 90 : 8581 8585.[PubMed] [CrossRef]
13. Tjelle TE,, Brech A,, Juvet LK,, Griffiths G,, Berg T . 1996. Isolation and characterization of early endosomes, late endosomes and terminal lysosomes: their role in protein degradation. J Cell Sci 109( Pt 12) : 2905 2914.[PubMed]
14. Shi GP,, Villadangos JA,, Dranoff G,, Small C,, Gu L,, Haley KJ,, Riese R,, Ploegh HL,, Chapman HA . 1999. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10 : 197 206.[PubMed] [CrossRef]
15. Nakagawa TY,, Brissette WH,, Lira PD,, Griffiths RJ,, Petrushova N,, Stock J,, McNeish JD,, Eastman SE,, Howard ED,, Clarke SR,, Rosloniec EF,, Elliott EA,, Rudensky AY . 1999. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity 10 : 207 217.[PubMed] [CrossRef]
16. Manoury B,, Mazzeo D,, Li DN,, Billson J,, Loak K,, Benaroch P,, Watts C . 2003. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity 18 : 489 498.[PubMed] [CrossRef]
17. Riberdy JM,, Newcomb JR,, Surman MJ,, Barbosa JA,, Cresswell P . 1992. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides. Nature 360 : 474 477.[PubMed] [CrossRef]
18. Denzin LK,, Cresswell P . 1995. HLA-DM induces CLIP dissociation from MHC class II αβ dimers and facilitates peptide loading. Cell 82 : 155 165.[PubMed] [CrossRef]
19. Marks MS,, Roche PA,, van Donselaar E,, Woodruff L,, Peters PJ,, Bonifacino JS . 1995. A lysosomal targeting signal in the cytoplasmic tail of the β chain directs HLA-DM to MHC class II compartments. J Cell Biol 131 : 351 369.[PubMed] [CrossRef]
20. Kropshofer H,, Vogt AB,, Moldenhauer G,, Hammer J,, Blum JS,, Hammerling GJ . 1996. Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J 15 : 6144 6154.[PubMed]
21. Sant AJ,, Chaves FA,, Jenks SA,, Richards KA,, Menges P,, Weaver JM,, Lazarski CA . 2005. The relationship between immunodominance, DM editing, and the kinetic stability of MHC class II:peptide complexes. Immunol Rev 207 : 261 278.[PubMed] [CrossRef]
22. Yin L,, Stern LJ . 2013. HLA-DM focuses on conformational flexibility around P1 pocket to catalyze peptide exchange. Front Immunol 4 : 336. doi:10.3389/fimmu.2013.00336. [PubMed] [CrossRef]
23. Pos W,, Sethi DK,, Call MJ,, Schulze MS,, Anders AK,, Pyrdol J,, Wucherpfennig KW . 2012. Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 151 : 1557 1568.[PubMed] [CrossRef]
24. Liljedahl M,, Kuwana T,, Fung-Leung WP,, Jackson MR,, Peterson PA,, Karlsson L . 1996. HLA-DO is a lysosomal resident which requires association with HLA-DM for efficient intracellular transport. EMBO J 15 : 4817 4824.[PubMed]
25. Chen X,, Reed-Loisel LM,, Karlsson L,, Jensen PE . 2006. H2-O expression in primary dendritic cells. J Immunol 176 : 3548 3556.[PubMed] [CrossRef]
26. Fallas JL,, Yi W,, Draghi NA,, O’Rourke HM,, Denzin LK . 2007. Expression patterns of H2-O in mouse B cells and dendritic cells correlate with cell function. J Immunol 178 : 1488 1497.[PubMed] [CrossRef]
27. Hornell TM,, Burster T,, Jahnsen FL,, Pashine A,, Ochoa MT,, Harding JJ,, Macaubas C,, Lee AW,, Modlin RL,, Mellins ED . 2006. Human dendritic cell expression of HLA-DO is subset specific and regulated by maturation. J Immunol 176 : 3536 3547.[PubMed] [CrossRef]
28. Denzin LK,, Fallas JL,, Prendes M,, Yi W . 2005. Right place, right time, right peptide: DO keeps DM focused. Immunol Rev 207 : 279 292.[PubMed] [CrossRef]
29. Liljedahl M,, Winqvist O,, Surh CD,, Wong P,, Ngo K,, Teyton L,, Peterson PA,, Brunmark A,, Rudensky AY,, Fung-Leung WP,, Karlsson L . 1998. Altered antigen presentation in mice lacking H2-O. Immunity 8 : 233 243.[PubMed] [CrossRef]
30. Hinz A,, Tampe R . 2012. ABC transporters and immunity: mechanism of self-defense. Biochemistry 51 : 4981 4989.[PubMed] [CrossRef]
31. Saveanu L,, Carroll O,, Lindo V,, Del Val M,, Lopez D,, Lepelletier Y,, Greer F,, Schomburg L,, Fruci D,, Niedermann G,, van Endert PM . 2005. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol 6 : 689 697.[PubMed] [CrossRef]
32. Blum JS,, Wearsch PA,, Cresswell P . 2013. Pathways of antigen processing. Annu Rev Immunol 31 : 443 473.[PubMed] [CrossRef]
33. Hebert DN,, Garman SC,, Molinari M . 2005. The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags. Trends Cell Biol 15 : 364 370.[PubMed] [CrossRef]
34. D’Alessio C,, Caramelo JJ,, Parodi AJ . 2010. UDP-GlC:glycoprotein glucosyltransferase-glucosidase II, the ying-yang of the ER quality control. Seminars Cell Dev Biol 21 : 491 499.[PubMed] [CrossRef]
35. Gao B,, Adhikari R,, Howarth M,, Nakamura K,, Gold MC,, Hill AB,, Knee R,, Michalak M,, Elliott T . 2002. Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. Immunity 16 : 99 109.[PubMed] [CrossRef]
36. Garbi N,, Tanaka S,, Momburg F,, Hammerling GJ . 2006. Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57. Nat Immunol 7 : 93 102.[PubMed] [CrossRef]
37. Zhang W,, Wearsch PA,, Zhu Y,, Leonhardt RM,, Cresswell P . 2011. A role for UDP-glucose glycoprotein glucosyltransferase in expression and quality control of MHC class I molecules. Proc Natl Acad Sci U S A 108 : 4956 4961.[PubMed] [CrossRef]
38. Williams AP,, Peh CA,, Purcell AW,, McCluskey J,, Elliott T . 2002. Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity 16 : 509 520.[CrossRef]
39. Howarth M,, Williams A,, Tolstrup AB,, Elliott T . 2004. Tapasin enhances MHC class I peptide presentation according to peptide half-life. Proc Natl Acad Sci U S A 101 : 11737 11742.[PubMed] [CrossRef]
40. Wearsch PA,, Cresswell P . 2007. Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer. Nat Immunol 8 : 873 881.[PubMed] [CrossRef]
41. Joffre OP,, Segura E,, Savina A,, Amigorena S . 2012. Cross-presentation by dendritic cells. Nat Rev Immunol 12 : 557 569.[PubMed] [CrossRef]
42. Shen L,, Sigal LJ,, Boes M,, Rock KL . 2004. Important role of cathepsin S in generating peptides for TAP-independent MHC class I crosspresentation in vivo. Immunity 21 : 155 165.[PubMed] [CrossRef]
43. den Haan JM,, Lehar SM,, Bevan MJ . 2000. CD8 + but not CD8 dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 192 : 1685 1696.[PubMed] [CrossRef]
44. Jongbloed SL,, Kassianos AJ,, McDonald KJ,, Clark GJ,, Ju X,, Angel CE,, Chen CJ,, Dunbar PR,, Wadley RB,, Jeet V,, Vulink AJ,, Hart DN,, Radford KJ . 2010. Human CD141 + (BDCA-3) + dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med 207 : 1247 1260.[PubMed] [CrossRef]
45. Poulin LF,, Salio M,, Griessinger E,, Anjos-Afonso F,, Craciun L,, Chen JL,, Keller AM,, Joffre O,, Zelenay S,, Nye E,, Le Moine A,, Faure F,, Donckier V,, Sancho D,, Cerundolo V,, Bonnet D,, Reis e Sousa C . 2010. Characterization of human DNGR-1 + BDCA3 + leukocytes as putative equivalents of mouse CD8α + dendritic cells. J Exp Med 207 : 1261 1271.[PubMed] [CrossRef]
46. Segura E,, Durand M,, Amigorena S . 2013. Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ-resident dendritic cells. J Exp Med 210 : 1035 1047.[PubMed] [CrossRef]
47. Lim JP,, Gleeson PA . 2011. Macropinocytosis: an endocytic pathway for internalising large gulps. Immunol Cell Biol 89 : 836 843.[PubMed] [CrossRef]
48. Norbury CC,, Chambers BJ,, Prescott AR,, Ljunggren HG,, Watts C . 1997. Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur J Immunol 27 : 280 288.[PubMed] [CrossRef]
49. Garrett WS,, Chen LM,, Kroschewski R,, Ebersold M,, Turley S,, Trombetta S,, Galan JE,, Mellman I . 2000. Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102 : 325 334.[PubMed] [CrossRef]
50. West MA,, Prescott AR,, Eskelinen EL,, Ridley AJ,, Watts C . 2000. Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation. Curr Biol 10 : 839 848.[PubMed] [CrossRef]
51. Ruedl C,, Koebel P,, Karjalainen K . 2001. In vivo-matured Langerhans cells continue to take up and process native proteins unlike in vitro-matured counterparts. J Immunol 166 : 7178 7182.[PubMed] [CrossRef]
52. Platt CD,, Ma JK,, Chalouni C,, Ebersold M,, Bou-Reslan H,, Carano RA,, Mellman I,, Delamarre L . 2010. Mature dendritic cells use endocytic receptors to capture and present antigens. Proc Natl Acad Sci U S A 107 : 4287 4292.[PubMed] [CrossRef]
53. Drutman SB,, Trombetta ES . 2010. Dendritic cells continue to capture and present antigens after maturation in vivo. J Immunol 185 : 2140 2146.[PubMed] [CrossRef]
54. Jayachandran R,, Sundaramurthy V,, Combaluzier B,, Mueller P,, Korf H,, Huygen K,, Miyazaki T,, Albrecht I,, Massner J,, Pieters J . 2007. Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 130 : 37 50.[PubMed] [CrossRef]
55. Bosedasgupta S,, Pieters J . 2014. Inflammatory stimuli reprogram macrophage phagocytosis to macropinocytosis for the rapid elimination of pathogens. PLoS Pathog 10 : e1003879. doi:10.1371/journal.ppat.1003879. [PubMed] [CrossRef]
56. Bonifaz LC,, Bonnyay DP,, Charalambous A,, Darguste DI,, Fujii S,, Soares H,, Brimnes MK,, Moltedo B,, Moran TM,, Steinman RM . 2004. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 199 : 815 824.[PubMed] [CrossRef]
57. Chatterjee B,, Smed-Sörensen A,, Cohn L,, Chalouni C,, Vandlen R,, Lee BC,, Widger J,, Keler T,, Delamarre L,, Mellman I . 2012. Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells. Blood 120 : 2011 2020.[PubMed] [CrossRef]
58. Stuart LM,, Ezekowitz RA . 2005. Phagocytosis: elegant complexity. Immunity 22 : 539 550.[PubMed] [CrossRef]
59. Gagnon E,, Duclos S,, Rondeau C,, Chevet E,, Cameron PH,, Steele-Mortimer O,, Paiement J,, Bergeron JJ,, Desjardins M . 2002. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110 : 119 131.[CrossRef]
60. Ackerman AL,, Kyritsis C,, Tampe R,, Cresswell P . 2003. Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc Natl Acad Sci U S A 100 : 12889 12894.[PubMed] [CrossRef]
61. Guermonprez P,, Saveanu L,, Kleijmeer M,, Davoust J,, Van Endert P,, Amigorena S . 2003. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425 : 397 402.[PubMed] [CrossRef]
62. Houde M,, Bertholet S,, Gagnon E,, Brunet S,, Goyette G,, Laplante A,, Princiotta MF,, Thibault P,, Sacks D,, Desjardins M . 2003. Phagosomes are competent organelles for antigen cross-presentation. Nature 425 : 402 406.[PubMed] [CrossRef]
63. Nair-Gupta P,, Baccarini A,, Tung N,, Seyffer F,, Florey O,, Huang Y,, Banerjee M,, Overholtzer M,, Roche PA,, Tampe R,, Brown BD,, Amsen D,, Whiteheart SW,, Blander JM . 2014. TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 158 : 506 521.[PubMed] [CrossRef]
64. Blander JM,, Medzhitov R . 2004. Regulation of phagosome maturation by signals from Toll-like receptors. Science 304 : 1014 1018.[PubMed] [CrossRef]
65. Blander JM,, Medzhitov R . 2006. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440 : 808 812.[PubMed] [CrossRef]
66. Savina A,, Jancic C,, Hugues S,, Guermonprez P,, Vargas P,, Moura IC,, Lennon-Duménil AM,, Seabra MC,, Raposo G,, Amigorena S . 2006. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126 : 205 218.[PubMed] [CrossRef]
67. Savina A,, Peres A,, Cebrian I,, Carmo N,, Moita C,, Hacohen N,, Moita LF,, Amigorena S . 2009. The small GTPase Rac2 controls phagosomal alkalinization and antigen crosspresentation selectively in CD8 + dendritic cells. Immunity 30 : 544 555.[PubMed] [CrossRef]
68. Crotzer VL,, Blum JS . 2010. Autophagy and adaptive immunity. Immunology 131 : 9 17.[PubMed] [CrossRef]
69. Schmid D,, Pypaert M,, Munz C . 2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26 : 79 92.[PubMed] [CrossRef]
70. Adamopoulou E,, Tenzer S,, Hillen N,, Klug P,, Rota IA,, Tietz S,, Gebhardt M,, Stevanovic S,, Schild H,, Tolosa E,, Melms A,, Stoeckle C . 2013. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat Commun 4 : 2039. doi:10.1038/ncomms3039. [CrossRef]
71. Nedjic J,, Aichinger M,, Emmerich J,, Mizushima N,, Klein L . 2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455 : 396 400.[PubMed] [CrossRef]
72. Aichinger M,, Wu C,, Nedjic J,, Klein L . 2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J Exp Med 210 : 287 300.[PubMed] [CrossRef]
73. Kaushik S,, Cuervo AM . 2012. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 22 : 407 417.[PubMed] [CrossRef]
74. Manoury B,, Mazzeo D,, Fugger L,, Viner N,, Ponsford M,, Streeter H,, Mazza G,, Wraith DC,, Watts C . 2002. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 3 : 169 174.[PubMed] [CrossRef]
75. Delamarre L,, Pack M,, Chang H,, Mellman I,, Trombetta ES . 2005. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307 : 1630 1634.[PubMed] [CrossRef]
76. Trombetta ES,, Ebersold M,, Garrett W,, Pypaert M,, Mellman I . 2003. Activation of lysosomal function during dendritic cell maturation. Science 299 : 1400 1403.[PubMed] [CrossRef]
77. Sardiello M,, Palmieri M,, di Ronza A,, Medina DL,, Valenza M,, Gennarino VA,, Di Malta C,, Donaudy F,, Embrione V,, Polishchuk RS,, Banfi S,, Parenti G,, Cattaneo E,, Ballabio A . 2009. A gene network regulating lysosomal biogenesis and function. Science 325 : 473 477.[PubMed] [CrossRef]
78. Settembre C,, Fraldi A,, Medina DL,, Ballabio A . 2013. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14 : 283 296.[PubMed] [CrossRef]
79. Inaba K,, Turley S,, Iyoda T,, Yamaide F,, Shimoyama S,, Reis e Sousa C,, Germain RN,, Mellman I,, Steinman RM . 2000. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J Exp Med 191 : 927 936.[PubMed] [CrossRef]
80. Turley SJ,, Inaba K,, Garrett WS,, Ebersold M,, Unternaehrer J,, Steinman RM,, Mellman I . 2000. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288 : 522 527.[PubMed] [CrossRef]
81. Lautwein A,, Burster T,, Lennon-Duménil AM,, Overkleeft HS,, Weber E,, Kalbacher H,, Driessen C . 2002. Inflammatory stimuli recruit cathepsin activity to late endosomal compartments in human dendritic cells. Eur J Immunol 32 : 3348 3357.[PubMed] [CrossRef]
82. Kleijmeer MJ,, Oorschot VM,, Geuze HJ . 1994. Human resident Langerhans cells display a lysosomal compartment enriched in MHC class II. J Invest Dermatol 103 : 516 523.[PubMed] [CrossRef]
83. Stang E,, Guerra CB,, Amaya M,, Paterson Y,, Bakke O,, Mellins ED . 1998. DR/CLIP (class II-associated invariant chain peptides) and DR/peptide complexes colocalize in prelysosomes in human B lymphoblastoid cells. J Immunol 160 : 4696 4707.[PubMed]
84. Kleijmeer M,, Ramm G,, Schuurhuis D,, Griffith J,, Rescigno M,, Ricciardi-Castagnoli P,, Rudensky AY,, Ossendorp F,, Melief CJ,, Stoorvogel W,, Geuze HJ . 2001. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J Cell Biol 155 : 53 63.[PubMed] [CrossRef]
85. Denzer K,, Kleijmeer MJ,, Heijnen HF,, Stoorvogel W,, Geuze HJ . 2000. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113( Pt 19) : 3365 3374.[PubMed]
86. Zitvogel L,, Regnault A,, Lozier A,, Wolfers J,, Flament C,, Tenza D,, Ricciardi-Castagnoli P,, Raposo G,, Amigorena S . 1998. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4 : 594 600.[PubMed] [CrossRef]
87. Thery C,, Duban L,, Segura E,, Veron P,, Lantz O,, Amigorena S . 2002. Indirect activation of naive CD4 + T cells by dendritic cell-derived exosomes. Nat Immunol 3 : 1156 1162.[PubMed] [CrossRef]
88. Buschow SI,, Nolte-’t Hoen EN,, van Niel G,, Pols MS,, ten Broeke T,, Lauwen M,, Ossendorp F,, Melief CJ,, Raposo G,, Wubbolts R,, Wauben MH,, Stoorvogel W . 2009. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10 : 1528 1542.[PubMed] [CrossRef]
89. Chow A,, Toomre D,, Garrett W,, Mellman I . 2002. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418 : 988 994.[PubMed] [CrossRef]
90. Boes M,, Cerny J,, Massol R,, Op den Brouw M,, Kirchhausen T,, Chen J,, Ploegh HL . 2002. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418 : 983 988.[PubMed] [CrossRef]
91. Wubbolts R,, Fernandez-Borja M,, Oomen L,, Verwoerd D,, Janssen H,, Calafat J,, Tulp A,, Dusseljee S,, Neefjes J . 1996. Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J Cell Biol 135 : 611 622.[PubMed] [CrossRef]
92. Rocha N,, Neefjes J . 2008. MHC class II molecules on the move for successful antigen presentation. EMBO J 27 : 1 5.[PubMed] [CrossRef]
93. Bosch B,, Heipertz EL,, Drake JR,, Roche PA . 2013. Major histocompatibility complex (MHC) class II-peptide complexes arrive at the plasma membrane in cholesterol-rich microclusters. J Biol Chem 288 : 13236 13242.[PubMed] [CrossRef]
94. Anderson HA,, Roche PA . 2015. MHC class II association with lipid rafts on the antigen presenting cell surface. Biochim Biophys Acta 1853 : 775 780.[PubMed] [CrossRef]
95. Reith W,, LeibundGut-Landmann S,, Waldburger JM . 2005. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol 5 : 793 806.[PubMed] [CrossRef]
96. Cella M,, Engering A,, Pinet V,, Pieters J,, Lanzavecchia A . 1997. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388 : 782 787.[PubMed] [CrossRef]
97. Young LJ,, Wilson NS,, Schnorrer P,, Mount A,, Lundie RJ,, La Gruta NL,, Crabb BS,, Belz GT,, Heath WR,, Villadangos JA . 2007. Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens. Proc Natl Acad Sci U S A 104 : 17753 17758.[PubMed] [CrossRef]
98. Landmann S,, Muhlethaler-Mottet A,, Bernasconi L,, Suter T,, Waldburger JM,, Masternak K,, Arrighi JF,, Hauser C,, Fontana A,, Reith W . 2001. Maturation of dendritic cells is accompanied by rapid transcriptional silencing of class II transactivator (CIITA) expression. J Exp Med 194 : 379 391.[PubMed] [CrossRef]
99. Yao Y,, Xu Q,, Kwon MJ,, Matta R,, Liu Y,, Hong SC,, Chang CH . 2006. ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages. J Immunol 177 : 70 76.[PubMed] [CrossRef]
100. De Gassart A,, Camosseto V,, Thibodeau J,, Ceppi M,, Catalan N,, Pierre P,, Gatti E . 2008. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc Natl Acad Sci U S A 105 : 3491 3496.[PubMed] [CrossRef]
101. Walseng E,, Furuta K,, Bosch B,, Weih KA,, Matsuki Y,, Bakke O,, Ishido S,, Roche PA . 2010. Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells. Proc Natl Acad Sci U S A 107 : 20465 20470.[PubMed] [CrossRef]
102. Pierre P,, Turley SJ,, Gatti E,, Hull M,, Meltzer J,, Mirza A,, Inaba K,, Steinman RM,, Mellman I . 1997. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388 : 787 792.[PubMed] [CrossRef]
103. Roche PA,, Furuta K . 2015. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15 : 203 216.[PubMed] [CrossRef]
104. Samie M,, Cresswell P . 2015. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways. Nat Immunol 16 : 729 736.[PubMed] [CrossRef]

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