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Towards a systems understanding of MHC class I and MHC class II antigen presentation

Key Points

  • MHC class I and MHC class II molecules have long been intensively studied, and this has resulted in a global view of these processes. New technologies, including genome-wide small interfering RNA screens and systems biology approaches, have identified numerous additional pathways that control antigen presentation by MHC molecules.

  • MHC molecules are polymorphic, and the biology of the various alleles differs, such that they can potentially have different consequences with regards to the relevant immune responses. This point is best-defined for MHC class I molecules. In this Review, we bring this into context with the current understanding of the general MHC class I antigen presentation process.

  • The biology of MHC molecules touches almost all areas in the field of cell biology. Various new findings from the area of cell biology have consequences for MHC class I and MHC class II antigen presentation.

  • The immune system is a relatively late addition in our progress through evolution, and many immune-specific molecules exist. Unique functions of some of these, including the immunoproteasome in interferon-induced damage clearance, have been recently uncovered.

  • Through a combination of small interfering RNA screens, microarrays and cell biological approaches, novel pathways that control MHC class II expression and transport in dendritic cells have been defined. The systems biology of MHC molecules will yield more surprises.

  • A dynamic field of research has many unsolved issues. A survey of the views of almost 50 group leaders in the field of antigen presentation has provided democratic opinions on the variety of unsettled topics within the field.

Abstract

The molecular details of antigen processing and presentation by MHC class I and class II molecules have been studied extensively for almost three decades. Although the basic principles of these processes were laid out approximately 10 years ago, the recent years have revealed many details and provided new insights into their control and specificity. MHC molecules use various biochemical reactions to achieve successful presentation of antigenic fragments to the immune system. Here we present a timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved. The continuing flow of new details into our understanding of the biology of MHC class I and class II antigen presentation builds a system involving several cell biological processes, which is discussed in this Review.

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Figure 1: The basic MHC class I antigen presentation pathway.
Figure 2: Complexity of the MHC class I antigen presentation pathway.
Figure 3: The basic MHC class II antigen presentation pathway.
Figure 4: Complexity of the MHC class II antigen presentation pathway.

References

  1. Vyas, J. M., Van der Veen, A. G. & Ploegh, H. L. The known unknowns of antigen processing and presentation. Nature Rev. Immunol. 8, 607–618 (2008).

    CAS  Article  Google Scholar 

  2. Kurts, C., Robinson, B. W. & Knolle, P. A. Cross-priming in health and disease. Nature Rev. Immunol. 10, 403–414 (2010).

    CAS  Article  Google Scholar 

  3. Crotzer, V. L. & Blum, J. S. Autophagy and adaptive immunity. Immunology 131, 9–17 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Horst, D., Verweij, M. C., Davison, A. J., Ressing, M. E. & Wiertz, E. J. Viral evasion of T cell immunity: ancient mechanisms offering new applications. Curr. Opin. Immunol. 23, 96–103 (2011).

    CAS  PubMed  Article  Google Scholar 

  5. Hughes, E. A., Hammond, C. & Cresswell, P. Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proc. Natl Acad. Sci. USA 94, 1896–1901 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Koopmann, J. O. et al. Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel. Immunity 13, 117–127 (2000).

    CAS  Article  PubMed  Google Scholar 

  7. Reits, E. A., Vos, J. C., Gromme, M. & Neefjes, J. The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404, 774–778 (2000).

    CAS  PubMed  Article  Google Scholar 

  8. Schubert, U. et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774 (2000).

    CAS  PubMed  Article  Google Scholar 

  9. Li, M. et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science 333, 53–58 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Yewdell, J. W. & Hickman, H. D. New lane in the information highway: alternative reading frame peptides elicit T cells with potent antiretrovirus activity. J. Exp. Med. 204, 2501–2504 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Berglund, P., Finzi, D., Bennink, J. R. & Yewdell, J. W. Viral alteration of cellular translational machinery increases defective ribosomal products. J. Virol. 81, 7220–7229 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Netzer, N. et al. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 462, 522–526 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Dolan, B. P. et al. Distinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance. J. Immunol. 186, 2065–2072 (2011).

    CAS  PubMed  Article  Google Scholar 

  14. Khan, S. et al. Cutting edge: neosynthesis is required for the presentation of a T cell epitope from a long-lived viral protein. J. Immunol. 167, 4801–4804 (2001).

    CAS  PubMed  Article  Google Scholar 

  15. Vigneron, N. et al. An antigenic peptide produced by peptide splicing in the proteasome. Science 304, 587–590 (2004).

    CAS  PubMed  Article  Google Scholar 

  16. Hanada, K., Yewdell, J. W. & Yang, J. C. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427, 252–256 (2004).

    CAS  PubMed  Article  Google Scholar 

  17. Dalet, A. et al. An antigenic peptide produced by reverse splicing and double asparagine deamidation. Proc. Natl Acad. Sci. USA 108, e323–e331 (2011). References 9, 11 and 15–17 describe various examples of the generation of non-genetically encoded antigens that can be presented by MHC class I molecules.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. Neefjes, J. J. & Ploegh, H. L. Allele and locus-specific differences in cell surface expression and the association of HLA class I heavy chain with β2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur. J. Immunol. 18, 801–810 (1988).

    CAS  PubMed  Article  Google Scholar 

  19. Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Kulkarni, S. et al. Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature 472, 495–498 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Apcher, S. et al. Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. Proc. Natl Acad. Sci. USA 108, 11572–11577 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Gu, W. et al. Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses. Proc. Natl Acad. Sci. USA 106, 8314–8319 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. Ferrara, T. A., Hodge, J. W. & Gulley, J. L. Combining radiation and immunotherapy for synergistic antitumor therapy. Curr. Opin. Mol. Ther. 11, 37–42 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mester, G., Hoffmann, V. & Stevanovic, S. Insights into MHC class I antigen processing gained from large-scale analysis of class I ligands. Cell. Mol. Life Sci. 68, 1521–1532 (2011).

    CAS  PubMed  Article  Google Scholar 

  25. Sauer, R. T. & Baker, T. A. AAA+ proteases: ATP-fueled machines of protein destruction. Annu. Rev. Biochem. 80, 587–612 (2011).

    CAS  PubMed  Article  Google Scholar 

  26. Cascio, P., Hilton, C., Kisselev, A. F., Rock, K. L. & Goldberg, A. L. 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J. 20, 2357–2366 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Sijts, E. J. & Kloetzel, P. M. The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell. Mol. Life Sci. 68, 1491–1502 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Toes, R. E. et al. Discrete cleavage motifs of constitutive and immunoproteasomes revealed by quantitative analysis of cleavage products. J. Exp. Med. 194, 1–12 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).

    CAS  Article  PubMed  Google Scholar 

  30. Seifert, U. et al. Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142, 613–624 (2010). This paper shows how immunological stress induces protein aggregation and pathology. Immunoproteasomes are more active than constitutive proteasomes and prevent aggregation and pathology.

    CAS  Article  PubMed  Google Scholar 

  31. Reits, E. et al. Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18, 97–108 (2003).

    CAS  PubMed  Article  Google Scholar 

  32. Wearsch, P. A. & Cresswell, P. The quality control of MHC class I peptide loading. Curr. Opin. Cell Biol. 20, 624–631 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Park, B. et al. Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing. Cell 127, 369–382 (2006).

    CAS  PubMed  Article  Google Scholar 

  34. Wearsch, P. A., Peaper, D. R. & Cresswell, P. Essential glycan-dependent interactions optimize MHC class I peptide loading. Proc. Natl Acad. Sci. USA 108, 4950–4955 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. Zarling, A. L. et al. Tapasin is a facilitator, not an editor, of class I MHC peptide binding. J. Immunol. 171, 5287–5295 (2003).

    CAS  PubMed  Article  Google Scholar 

  36. Parcej, D. & Tampe, R. ABC proteins in antigen translocation and viral inhibition. Nature Chem. Biol. 6, 572–580 (2010).

    CAS  Article  Google Scholar 

  37. Blanchard, N. et al. Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. J. Immunol. 184, 3033–3042 (2010).

    CAS  PubMed  Article  Google Scholar 

  38. Serwold, T., Gonzalez, F., Kim, J., Jacob, R. & Shastri, N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480–483 (2002).

    CAS  PubMed  Article  Google Scholar 

  39. Saveanu, L. et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nature Immunol. 6, 689–697 (2005).

    CAS  Article  Google Scholar 

  40. Saric, T. et al. An IFN-γ-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nature Immunol. 3, 1169–1176 (2002).

    CAS  Article  Google Scholar 

  41. York, I. A. et al. The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nature Immunol. 3, 1177–1184 (2002).

    CAS  Article  Google Scholar 

  42. Roelse, J., Gromme, M., Momburg, F., Hammerling, G. & Neefjes, J. Trimming of TAP-translocated peptides in the endoplasmic reticulum and in the cytosol during recycling. J. Exp. Med. 180, 1591–1597 (1994).

    CAS  PubMed  Article  Google Scholar 

  43. Neijssen, J. et al. Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434, 83–88 (2005).

    CAS  Article  PubMed  Google Scholar 

  44. Pang, B. et al. Direct antigen presentation and gap junction mediated cross-presentation during apoptosis. J. Immunol. 183, 1083–1090 (2009).

    CAS  PubMed  Article  Google Scholar 

  45. Saccheri, F. et al. Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity. Sci. Transl. Med. 2, 44ra57 (2010). This study shows that gap junctions are induced by S . Typhimurium infection and are essential for generating a strong antitumour response with a S . Typhimurium-based antitumour vaccine.

    PubMed  Article  Google Scholar 

  46. Trowsdale, J. HLA genomics in the third millennium. Curr. Opin. Immunol. 17, 498–504 (2005).

    CAS  PubMed  Article  Google Scholar 

  47. Neisig, A., Melief, C. J. & Neefjes, J. Reduced cell surface expression of HLA-C molecules correlates with restricted peptide binding and stable TAP interaction. J. Immunol. 160, 171–179 (1998).

    CAS  PubMed  Google Scholar 

  48. Neisig, A., Wubbolts, R., Zang, X., Melief, C. & Neefjes, J. Allele-specific differences in the interaction of MHC class I molecules with transporters associated with antigen processing. J. Immunol. 156, 3196–3206 (1996).

    CAS  PubMed  Google Scholar 

  49. Peh, C. A. et al. HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity 8, 531–542 (1998).

    CAS  PubMed  Article  Google Scholar 

  50. Leslie, A. et al. Additive contribution of HLA class I alleles in the immune control of HIV-1 infection. J. Virol. 84, 9879–9888 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Malik, P., Klimovitsky, P., Deng, L. W., Boyson, J. E. & Strominger, J. L. Uniquely conformed peptide-containing β2-microglobulin-free heavy chains of HLA-B2705 on the cell surface. J. Immunol. 169, 4379–4387 (2002).

    CAS  Article  PubMed  Google Scholar 

  52. Herberts, C. A. et al. Cutting edge: HLA-B27 acquires many N-terminal dibasic peptides: coupling cytosolic peptide stability to antigen presentation. J. Immunol. 176, 2697–2701 (2006).

    CAS  Article  PubMed  Google Scholar 

  53. Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genet. 43, 761–767 (2011).

    CAS  Article  PubMed  Google Scholar 

  54. Princiotta, M. F. et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity 18, 343–354 (2003).

    CAS  PubMed  Article  Google Scholar 

  55. Yewdell, J. W., Reits, E. & Neefjes, J. Making sense of mass destruction: quantitating MHC class I antigen presentation. Nature Rev. Immunol. 3, 952–961 (2003).

    CAS  Article  Google Scholar 

  56. Reits, E. A., Vos, J. C., Gromme, M. & Neefjes, J. The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404, 774–778 (2000).

    CAS  PubMed  Article  Google Scholar 

  57. Reits, E. et al. A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20, 495–506 (2004).

    CAS  PubMed  Article  Google Scholar 

  58. York, I. A., Bhutani, N., Zendzian, S., Goldberg, A. L. & Rock, K. L. Tripeptidyl peptidase II is the major peptidase needed to trim long antigenic precursors, but is not required for most MHC class I antigen presentation. J. Immunol. 177, 1434–1443 (2006).

    CAS  PubMed  Article  Google Scholar 

  59. Kloetzel, P. M. Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nature Immunol. 5, 661–669 (2004).

    CAS  Article  Google Scholar 

  60. Kessler, J. H. et al. Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunol. 12, 45–53 (2011).

    CAS  Article  Google Scholar 

  61. Kawahara, M., York, I. A., Hearn, A., Farfan, D. & Rock, K. L. Analysis of the role of tripeptidyl peptidase II in MHC class I antigen presentation in vivo. J. Immunol. 183, 6069–6077 (2009).

    CAS  PubMed  Article  Google Scholar 

  62. Saveanu, L., Carroll, O., Hassainya, Y. & van Endert, P. Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation. Immunol. Rev. 207, 42–59 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. Lev, A. et al. The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. Immunity 28, 787–798 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Lev, A. et al. Compartmentalized MHC class I antigen processing enhances immunosurveillance by circumventing the law of mass action. Proc. Natl Acad. Sci. USA 107, 6964–6969 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. Hessa, T. et al. Protein targeting and degradation are coupled for elimination of mislocalized proteins. Nature 475, 394–397 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Tenzer, S. et al. Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding. Cell. Mol. Life Sci. 62, 1025–1037 (2005).

    CAS  PubMed  Article  Google Scholar 

  67. Lundegaard, C., Lund, O., Buus, S. & Nielsen, M. Major histocompatibility complex class I binding predictions as a tool in epitope discovery. Immunology 130, 309–318 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Martayan, A. et al. Class I HLA folding and antigen presentation in β2-microglobulin-defective Daudi cells. J. Immunol. 182, 3609–3617 (2009).

    CAS  PubMed  Article  Google Scholar 

  69. Gromme, M. et al. Recycling MHC class I molecules and endosomal peptide loading. Proc. Natl Acad. Sci. USA 96, 10326–10331 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. Rocca, A. et al. Localization of the conformational alteration of MHC molecules induced by the association of mouse class I heavy chain with a xenogeneic β2-microglobulin. Mol. Immunol. 29, 481–487 (1992).

    CAS  PubMed  Article  Google Scholar 

  71. Neefjes, J. J., Smit, L., Gehrmann, M. & Ploegh, H. L. The fate of the three subunits of major histocompatibility complex class I molecules. Eur. J. Immunol. 22, 1609–1614 (1992).

    CAS  PubMed  Article  Google Scholar 

  72. Boname, J. M. et al. Efficient internalization of MHC I requires lysine-11 and lysine-63 mixed linkage polyubiquitin chains. Traffic 11, 210–220 (2010).

    CAS  PubMed  Article  Google Scholar 

  73. Bartee, E., Mansouri, M., Hovey Nerenberg, B. T., Gouveia, K. & Fruh, K. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J. Virol. 78, 1109–1120 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Howe, C. et al. Calreticulin-dependent recycling in the early secretory pathway mediates optimal peptide loading of MHC class I molecules. EMBO J. 28, 3730–3744 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Fernando, M. M. et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 4, e1000024 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. Anders, A. K. et al. HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide. Nature Immunol. 12, 54–61 (2011).

    CAS  Article  Google Scholar 

  77. Denzin, L. K., Fallas, J. L., Prendes, M. & Yi, W. Right place, right time, right peptide: DO keeps DM focused. Immunol. Rev. 207, 279–292 (2005).

    CAS  PubMed  Article  Google Scholar 

  78. Romieu-Mourez, R., Francois, M., Boivin, M. N., Stagg, J. & Galipeau, J. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-γ, TGF-β, and cell density. J. Immunol. 179, 1549–1558 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. Geppert, T. D. & Lipsky, P. E. Antigen presentation by interferon-γ-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression. J. Immunol. 135, 3750–3762 (1985).

    CAS  PubMed  Google Scholar 

  80. Bland, P. MHC class II expression by the gut epithelium. Immunol. Today 9, 174–178 (1988).

    CAS  PubMed  Article  Google Scholar 

  81. Koretz, K., Leman, J., Brandt, I. & Moller, P. Metachromasia of 3-amino-9-ethylcarbazole (AEC) and its prevention in immunoperoxidase techniques. Histochemistry 86, 471–478 (1987).

    CAS  PubMed  Article  Google Scholar 

  82. Mulder, D. J. et al. Antigen presentation and MHC class II expression by human esophageal epithelial cells: role in eosinophilic esophagitis. Am. J. Pathol. 178, 744–753 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Schonefuss, A. et al. Upregulation of cathepsin S in psoriatic keratinocytes. Exp. Dermatol. 19, e80–e88 (2010).

    PubMed  Article  Google Scholar 

  84. Tjernlund, U. M., Scheynius, A., Kabelitz, D. & Klareskog, L. Anti-Ia-reactive cells in mycosis fungoides: a study of skin biopsies, single epidermal cells and circulating T lymphocytes. Acta Derm. Venereol. 61, 291–301 (1981).

    CAS  PubMed  Google Scholar 

  85. Choi, N. M., Majumder, P. & Boss, J. M. Regulation of major histocompatibility complex class II genes. Curr. Opin. Immunol. 23, 81–87 (2011).

    CAS  PubMed  Article  Google Scholar 

  86. Muhlethaler-Mottet, A., Otten, L. A., Steimle, V. & Mach, B. Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J. 16, 2851–2860 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Reith, W., LeibundGut-Landmann, S. & Waldburger, J. M. Regulation of MHC class II gene expression by the class II transactivator. Nature Rev. Immunol. 5, 793–806 (2005).

    CAS  Article  Google Scholar 

  88. Smith, M. A. et al. Positive regulatory domain I (PRDM1) and IRF8/Pu.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. J. Biol. Chem. 286, 7893–7904 (2011). A study of the transcriptional regulation of MHC class II expression in immature and mature DCs.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Sisk, T. J., Nickerson, K., Kwok, R. P. & Chang, C. H. Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int. Immunol. 15, 1195–1205 (2003).

    CAS  PubMed  Article  Google Scholar 

  90. Greer, S. F. et al. Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. J. Immunol. 173, 376–383 (2004).

    CAS  PubMed  Article  Google Scholar 

  91. Bhat, K. P., Truax, A. D. & Greer, S. F. Phosphorylation and ubiquitination of degron proximal residues are essential for class II transactivator (CIITA) transactivation and major histocompatibility class II expression. J. Biol. Chem. 285, 25893–25903 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Greer, S. F., Zika, E., Conti, B., Zhu, X. S. & Ting, J. P. Enhancement of CIITA transcriptional function by ubiquitin. Nature Immunol. 4, 1074–1082 (2003).

    CAS  Article  Google Scholar 

  93. Paul, P. et al. A genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell 145, 268–283 (2011). A genome-wide siRNA screen for factors that control expression and peptide loading of MHC class II molecules. Many unknown factors are identified and additional screens are presented to reveal new pathways controlling MHC class II expression and transport in immature DCs.

    CAS  PubMed  Article  Google Scholar 

  94. Busch, R., Doebele, R. C., Patil, N. S., Pashine, A. & Mellins, E. D. Accessory molecules for MHC class II peptide loading. Curr. Opin. Immunol. 12, 99–106 (2000).

    CAS  PubMed  Article  Google Scholar 

  95. Bertolino, P. & Rabourdin-Combe, C. The MHC class II-associated invariant chain: a molecule with multiple roles in MHC class II biosynthesis and antigen presentation to CD4+ T cells. Crit. Rev. Immunol. 16, 359–379 (1996).

    CAS  PubMed  Google Scholar 

  96. Landsverk, O. J., Bakke, O. & Gregers, T. F. MHC II and the endocytic pathway: regulation by invariant chain. Scand. J. Immunol. 70, 184–193 (2009).

    CAS  PubMed  Article  Google Scholar 

  97. Bodmer, H., Viville, S., Benoist, C. & Mathis, D. Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science 263, 1284–1286 (1994).

    CAS  PubMed  Article  Google Scholar 

  98. Viville, S. et al. Mice lacking the MHC class II-associated invariant chain. Cell 72, 635–648 (1993).

    CAS  PubMed  Article  Google Scholar 

  99. Bikoff, E. K. et al. Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J. Exp. Med. 177, 1699–1712 (1993).

    CAS  PubMed  Article  Google Scholar 

  100. Tewari, M. K., Sinnathamby, G., Rajagopal, D. & Eisenlohr, L. C. A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent. Nature Immunol. 6, 287–294 (2005).

    CAS  Article  Google Scholar 

  101. Hofmann, M. W. et al. The leucine-based sorting motifs in the cytoplasmic domain of the invariant chain are recognized by the clathrin adaptors AP1 and AP2 and their medium chains. J. Biol. Chem. 274, 36153–36158 (1999).

    CAS  PubMed  Article  Google Scholar 

  102. Dugast, M., Toussaint, H., Dousset, C. & Benaroch, P. 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 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. McCormick, P. J., Martina, J. A. & Bonifacino, J. S. Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments. Proc. Natl Acad. Sci. USA 102, 7910–7915 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. Santambrogio, L. et al. Involvement of caspase-cleaved and intact adaptor protein 1 complex in endosomal remodeling in maturing dendritic cells. Nature Immunol. 6, 1020–1028 (2005).

    CAS  Article  Google Scholar 

  105. Peters, P. J., Neefjes, J. J., Oorschot, V., Ploegh, H. L. & Geuze, H. J. Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments. Nature 349, 669–676 (1991).

    CAS  PubMed  Article  Google Scholar 

  106. Sanderson, F. et al. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science 266, 1566–1569 (1994).

    CAS  PubMed  Article  Google Scholar 

  107. Kropshofer, H. et al. Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J. 15, 6144–6154 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Engering, A. & Pieters, J. Association of distinct tetraspanins with MHC class II molecules at different subcellular locations in human immature dendritic cells. Int. Immunol. 13, 127–134 (2001).

    CAS  PubMed  Article  Google Scholar 

  109. Hsing, L. C. & Rudensky, A. Y. The lysosomal cysteine proteases in MHC class II antigen presentation. Immunol. Rev. 207, 229–241 (2005).

    CAS  Article  PubMed  Google Scholar 

  110. Hartman, I. Z. et al. A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. Nature Med. 16, 1333–1340 (2010).

    CAS  PubMed  Article  Google Scholar 

  111. Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).

    CAS  Article  PubMed  Google Scholar 

  112. Zwart, W. et al. Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape. Immunity 22, 221–233 (2005).

    CAS  PubMed  Article  Google Scholar 

  113. ten Broeke, T., van Niel, G., Wauben, M. H., Wubbolts, R. & Stoorvogel, W. Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions. Traffic 12, 1025–1036 (2011).

    CAS  PubMed  Article  Google Scholar 

  114. Neefjes, J. J., Stollorz, V., Peters, P. J., Geuze, H. J. & Ploegh, H. L. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell 61, 171–183 (1990).

    CAS  PubMed  Article  Google Scholar 

  115. Nordeng, T. W. et al. The cytoplasmic tail of invariant chain regulates endosome fusion and morphology. Mol. Biol. Cell 13, 1846–1856 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Landsverk, O. J., Barois, N., Gregers, T. F. & Bakke, O. Invariant chain increases the half-life of MHC II by delaying endosomal maturation. Immunol. Cell Biol. 89, 619–629 (2011).

    CAS  PubMed  Article  Google Scholar 

  117. Strong, B. S. & Unanue, E. R. Presentation of type B peptide–MHC complexes from hen egg white lysozyme by TLR ligands and type I IFNs independent of H2-DM regulation. J. Immunol. 187, 2193–2201 (2011).

    CAS  PubMed  Article  Google Scholar 

  118. Trombetta, E. S., Ebersold, M., Garrett, W., Pypaert, M. & Mellman, I. Activation of lysosomal function during dendritic cell maturation. Science 299, 1400–1403 (2003).

    CAS  Article  PubMed  Google Scholar 

  119. Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009). This study reveals the complex effects of motor regulation on the MIIC and other late endosomes. Cholesterol in late endosomes and/or the MIIC controls interactions with the ER protein VAPA, which removes the dynein motor from its receptor RILP, resulting in vesicle relocation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Kuipers, H. F. et al. Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains. Hum. Immunol. 66, 653–665 (2005).

    CAS  PubMed  Article  Google Scholar 

  121. Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787 (1997).

    CAS  PubMed  Google Scholar 

  122. Pierre, P. et al. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388, 787–792 (1997).

    CAS  PubMed  Article  Google Scholar 

  123. Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002).

    CAS  Article  PubMed  Google Scholar 

  124. Wubbolts, R. et al. Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J. Cell Biol. 135, 611–622 (1996).

    CAS  PubMed  Article  Google Scholar 

  125. Kleijmeer, M. et al. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J. Cell Biol. 155, 53–63 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Vascotto, F. et al. The actin-based motor protein myosin II regulates MHC class II trafficking and BCR-driven antigen presentation. J. Cell Biol. 176, 1007–1019 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nature Rev. Mol. Cell Biol. 10, 623–635 (2009).

    CAS  Article  Google Scholar 

  128. de Gassart, A. et al. 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. USA 105, 3491–3496 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. Shin, J. S. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444, 115–118 (2006).

    CAS  Article  PubMed  Google Scholar 

  130. Thibodeau, J. et al. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Eur. J. Immunol. 38, 1225–1230 (2008). This study explains the effects of IL-10 on MHC class II expression in human monocytes. IL-10 controls MARCH1 expression, which in turn controls the half-life of MHC class II on the cell surface.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Koppelman, B., Neefjes, J. J., de Vries, J. E. & Waal Malefyt, R. Interleukin-10 down-regulates MHC class II αβ peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7, 861–871 (1997).

    CAS  PubMed  Article  Google Scholar 

  132. Tze, L. E. et al. CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. J. Exp. Med. 208, 149–165 (2011). This study shows how CD83 inhibits MHC class II ubiquitylation by MARCH1.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. McGehee, A. M. et al. Ubiquitin-dependent control of class II MHC localization is dispensable for antigen presentation and antibody production. PLoS ONE 6, e18817 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Walseng, E. et al. Ubiquitination regulates MHC class II–peptide complex retention and degradation in dendritic cells. Proc. Natl Acad. Sci. USA 107, 20465–20470 (2010). This article shows how ubiquitylation regulates the degradation of internalized MHC class II molecules but not the endocytosis of MHC class II.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. Al Daccak, R., Mooney, N. & Charron, D. MHC class II signaling in antigen-presenting cells. Curr. Opin. Immunol. 16, 108–113 (2004).

    CAS  PubMed  Article  Google Scholar 

  136. Drenou, B. et al. A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes. J. Immunol. 163, 4115–4124 (1999).

    CAS  PubMed  Google Scholar 

  137. Hemon, P. et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186, 5173–5183 (2011).

    CAS  PubMed  Article  Google Scholar 

  138. Liu, X. et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nature Immunol. 12, 416–424 (2011). This comprehensive study reveals crosstalk between TLRs, MHC class II and CD40. A full mechanism is presented to describe how MHC class II molecules are involved in outside-in signalling.

    CAS  Article  Google Scholar 

  139. Lang, P. et al. TCR-induced transmembrane signaling by peptide/MHC class II via associated Ig-α/β dimers. Science 291, 1537–1540 (2001).

    CAS  PubMed  Article  Google Scholar 

  140. Bonnefoy, J. Y. et al. The low-affinity receptor for IgE (CD23) on B lymphocytes is spatially associated with HLA-DR antigens. J. Exp. Med. 167, 57–72 (1988).

    CAS  PubMed  Article  Google Scholar 

  141. Bradbury, L. E., Kansas, G. S., Levy, S., Evans, R. L. & Tedder, T. F. The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J. Immunol. 149, 2841–2850 (1992).

    CAS  PubMed  Google Scholar 

  142. van der Burg, S. H. & Melief, C. J. Therapeutic vaccination against human papilloma virus induced malignancies. Curr. Opin. Immunol. 23, 252–257 (2011).

    CAS  PubMed  Article  Google Scholar 

  143. Mitea, C. et al. A universal approach to eliminate antigenic properties of α-gliadin peptides in celiac disease. PLoS ONE 5, e15637 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Baugh, M. et al. Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity. J. Autoimmun. 36, 201–209 (2011).

    CAS  PubMed  Article  Google Scholar 

  145. Fallang, L. E. et al. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nature Immunol. 10, 1096–1101 (2009).

    CAS  Article  Google Scholar 

  146. Chow, K. M. et al. Studies on the subsite specificity of rat nardilysin (N-arginine dibasic convertase). J. Biol. Chem. 275, 19545–19551 (2000).

    CAS  PubMed  Article  Google Scholar 

  147. Chow, K. M. et al. Nardilysin cleaves peptides at monobasic sites. Biochemistry 42, 2239–2244 (2003).

    CAS  PubMed  Article  Google Scholar 

  148. York, I. A. et al. The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation. Immunity 18, 429–440 (2003).

    CAS  PubMed  Article  Google Scholar 

  149. Kim, S. I., Pabon, A., Swanson, T. A. & Glucksman, M. J. Regulation of cell-surface major histocompatibility complex class I expression by the endopeptidase EC3.4.24.15 (thimet oligopeptidase). Biochem. J. 375, 111–120 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Rock, K. L., York, I. A., Saric, T. & Goldberg, A. L. Protein degradation and the generation of MHC class I-presented peptides. Adv. Immunol. 80, 1–70 (2002).

    CAS  PubMed  Article  Google Scholar 

  151. Bhutani, N., Venkatraman, P. & Goldberg, A. L. Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation. EMBO J. 26, 1385–1396 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Stoltze, L. et al. Two new proteases in the MHC class I processing pathway. Nature Immunol. 1, 413–418 (2000).

    CAS  Article  Google Scholar 

  153. Parmentier, N. et al. Production of an antigenic peptide by insulin-degrading enzyme. Nature Immunol. 11, 449–454 (2010).

    CAS  Article  Google Scholar 

  154. Shen, X. Z., Lukacher, A. E., Billet, S., Williams, I. R. & Bernstein, K. E. Expression of angiotensin-converting enzyme changes major histocompatibility complex class I peptide presentation by modifying C termini of peptide precursors. J. Biol. Chem. 283, 9957–9965 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Chang, S. C., Momburg, F., Bhutani, N. & Goldberg, A. L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl Acad. Sci. USA 102, 17107–17112 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. Hammer, G. E., Gonzalez, F., James, E., Nolla, H. & Shastri, N. In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nature Immunol. 8, 101–108 (2007).

    CAS  Article  Google Scholar 

  157. Nguyen, T. T. et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nature Struct. Mol. Biol. 18, 604–613 (2011). References 39 and 155–157 show how ERAAP acts as a molecular ruler for MHC class I peptides and skews the peptide repertoire.

    CAS  Article  Google Scholar 

  158. Kreisel, D. et al. Cutting edge: MHC class II expression by pulmonary nonhematopoietic cells plays a critical role in controlling local inflammatory responses. J. Immunol. 185, 3809–3813 (2010).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We thank our colleagues for their input in the controversial items section and I. Berlin, S. van Kasteren, O. Landsverk and A. Lammerts van Beuren-Brandt for critical reading. We apologize to our colleagues for not citing every relevant paper owing to length limitations. This work was supported by European Research Council (ERC) and Netherlands Organization for Scientific Research (NWO) grants to J.N. and an NWO visiting grant to O.B.

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Glossary

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

Autophagy

Any process involving delivery of a portion of the cytoplasm to lysosomes that does not involve direct transport through the endocytic or vacuolar protein-sorting pathways.

DRiPs

(Defective ribosomal products). Misfolded proteins that result from defective transcription or translation.

Cytotoxic T lymphocytes

(CTLs). T cells that express the glycoprotein CD8 at the cell surface and that are capable of killing cells after recognizing peptides presented by MHC class I molecules.

Pulse-chase experiments

A method to examine a cellular process that occurs over time by following a molecule of interest, which is labelled at time-point zero.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase downstream of growth factors and nutrients (such as amino acids, glucose and oxygen).

microRNAs

Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

26S proteasome

A giant multicatalytic protease that resides in the cytosol and the nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins.

Thymic epithelial cells

(TECs). Cortical TECs promote the survival of thymocytes that possess T cell receptors that can bind to self MHC molecules. Medullary TECs induce apoptosis in thymocytes specific for self antigens.

HLA-DM

An MHC-like molecule that acts as a chaperone in MHC class II peptide loading.

Immunoribosomes

A subset of ribosomes that is thought to be responsible for the production of defective ribosomal products.

Crohn's disease

An inflammatory autoimmune disease of the gastrointestinal tract characterized by abdominal pain, vomiting and diarrhoea.

Tetraspanin

A member of a family of proteins that contain four transmembrane domains. Some tetraspanins are highly restricted to specific tissues, whereas others are widely distributed. Members of this family have been implicated in cell activation, proliferation, adhesion, motility, differentiation and cancer.

Endosomal sorting complex required for transport

(ESCRT). A complex of proteins required for the recognition and sorting of ubiquitin-modified proteins into the luminal vesicles of multivesicular bodies.

Exosomes

Small vesicles that are released from activated cells. They are bounded by a lipid bilayer that is derived either from the plasma membrane or from the membrane of internal vesicles of the MIIC.

Toll-like receptor

A member of a group of receptors that recognize components derived from a wide range of pathogens and switch on gene transcription that leads to cell activation and cytokine secretion.

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Neefjes, J., Jongsma, M., Paul, P. et al. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11, 823–836 (2011). https://doi.org/10.1038/nri3084

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