Review Article | Published:

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

Nature Reviews Immunology volume 11, pages 823836 (2011) | Download Citation

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.

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.

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References

  1. 1.

    , & The known unknowns of antigen processing and presentation. Nature Rev. Immunol. 8, 607–618 (2008).

  2. 2.

    , & Cross-priming in health and disease. Nature Rev. Immunol. 10, 403–414 (2010).

  3. 3.

    & Autophagy and adaptive immunity. Immunology 131, 9–17 (2010).

  4. 4.

    , , , & Viral evasion of T cell immunity: ancient mechanisms offering new applications. Curr. Opin. Immunol. 23, 96–103 (2011).

  5. 5.

    , & 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).

  6. 6.

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

  7. 7.

    , , & The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404, 774–778 (2000).

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

    , , & Viral alteration of cellular translational machinery increases defective ribosomal products. J. Virol. 81, 7220–7229 (2007).

  12. 12.

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

  13. 13.

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

  14. 14.

    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).

  15. 15.

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

  16. 16.

    , & Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427, 252–256 (2004).

  17. 17.

    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.

  18. 18.

    & 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).

  19. 19.

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

  20. 20.

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

  21. 21.

    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).

  22. 22.

    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).

  23. 23.

    , & Combining radiation and immunotherapy for synergistic antitumor therapy. Curr. Opin. Mol. Ther. 11, 37–42 (2009).

  24. 24.

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

  25. 25.

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

  26. 26.

    , , , & 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J. 20, 2357–2366 (2001).

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

    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.

  31. 31.

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

  32. 32.

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

  33. 33.

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

  34. 34.

    , & Essential glycan-dependent interactions optimize MHC class I peptide loading. Proc. Natl Acad. Sci. USA 108, 4950–4955 (2011).

  35. 35.

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

  36. 36.

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

  37. 37.

    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).

  38. 38.

    , , , & ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480–483 (2002).

  39. 39.

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

  40. 40.

    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).

  41. 41.

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

  42. 42.

    , , , & Trimming of TAP-translocated peptides in the endoplasmic reticulum and in the cytosol during recycling. J. Exp. Med. 180, 1591–1597 (1994).

  43. 43.

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

  44. 44.

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

  45. 45.

    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.

  46. 46.

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

  47. 47.

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

  48. 48.

    , , , & Allele-specific differences in the interaction of MHC class I molecules with transporters associated with antigen processing. J. Immunol. 156, 3196–3206 (1996).

  49. 49.

    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).

  50. 50.

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

  51. 51.

    , , , & Uniquely conformed peptide-containing β2-microglobulin-free heavy chains of HLA-B2705 on the cell surface. J. Immunol. 169, 4379–4387 (2002).

  52. 52.

    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).

  53. 53.

    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).

  54. 54.

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

  55. 55.

    , & Making sense of mass destruction: quantitating MHC class I antigen presentation. Nature Rev. Immunol. 3, 952–961 (2003).

  56. 56.

    , , & The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404, 774–778 (2000).

  57. 57.

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

  58. 58.

    , , , & 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).

  59. 59.

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

  60. 60.

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

  61. 61.

    , , , & Analysis of the role of tripeptidyl peptidase II in MHC class I antigen presentation in vivo. J. Immunol. 183, 6069–6077 (2009).

  62. 62.

    , , & Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation. Immunol. Rev. 207, 42–59 (2005).

  63. 63.

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

  64. 64.

    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).

  65. 65.

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

  66. 66.

    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).

  67. 67.

    , , & Major histocompatibility complex class I binding predictions as a tool in epitope discovery. Immunology 130, 309–318 (2010).

  68. 68.

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

  69. 69.

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

  70. 70.

    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).

  71. 71.

    , , & The fate of the three subunits of major histocompatibility complex class I molecules. Eur. J. Immunol. 22, 1609–1614 (1992).

  72. 72.

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

  73. 73.

    , , , & Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J. Virol. 78, 1109–1120 (2004).

  74. 74.

    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).

  75. 75.

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

  76. 76.

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

  77. 77.

    , , & Right place, right time, right peptide: DO keeps DM focused. Immunol. Rev. 207, 279–292 (2005).

  78. 78.

    , , , & 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).

  79. 79.

    & 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).

  80. 80.

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

  81. 81.

    , , & Metachromasia of 3-amino-9-ethylcarbazole (AEC) and its prevention in immunoperoxidase techniques. Histochemistry 86, 471–478 (1987).

  82. 82.

    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).

  83. 83.

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

  84. 84.

    , , & 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).

  85. 85.

    , & Regulation of major histocompatibility complex class II genes. Curr. Opin. Immunol. 23, 81–87 (2011).

  86. 86.

    , , & 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).

  87. 87.

    , & Regulation of MHC class II gene expression by the class II transactivator. Nature Rev. Immunol. 5, 793–806 (2005).

  88. 88.

    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.

  89. 89.

    , , & Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int. Immunol. 15, 1195–1205 (2003).

  90. 90.

    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).

  91. 91.

    , & 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).

  92. 92.

    , , , & Enhancement of CIITA transcriptional function by ubiquitin. Nature Immunol. 4, 1074–1082 (2003).

  93. 93.

    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.

  94. 94.

    , , , & Accessory molecules for MHC class II peptide loading. Curr. Opin. Immunol. 12, 99–106 (2000).

  95. 95.

    & 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).

  96. 96.

    , & MHC II and the endocytic pathway: regulation by invariant chain. Scand. J. Immunol. 70, 184–193 (2009).

  97. 97.

    , , & Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science 263, 1284–1286 (1994).

  98. 98.

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

  99. 99.

    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).

  100. 100.

    , , & A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent. Nature Immunol. 6, 287–294 (2005).

  101. 101.

    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).

  102. 102.

    , , & 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).

  103. 103.

    , & 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).

  104. 104.

    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).

  105. 105.

    , , , & 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).

  106. 106.

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

  107. 107.

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

  108. 108.

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

  109. 109.

    & The lysosomal cysteine proteases in MHC class II antigen presentation. Immunol. Rev. 207, 229–241 (2005).

  110. 110.

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

  111. 111.

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

  112. 112.

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

  113. 113.

    , , , & Endosomally stored MHC class II does not contribute to antigen presentation by dendritic cells at inflammatory conditions. Traffic 12, 1025–1036 (2011).

  114. 114.

    , , , & The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell 61, 171–183 (1990).

  115. 115.

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

  116. 116.

    , , & Invariant chain increases the half-life of MHC II by delaying endosomal maturation. Immunol. Cell Biol. 89, 619–629 (2011).

  117. 117.

    & 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).

  118. 118.

    , , , & Activation of lysosomal function during dendritic cell maturation. Science 299, 1400–1403 (2003).

  119. 119.

    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.

  120. 120.

    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).

  121. 121.

    , , , & Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787 (1997).

  122. 122.

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

  123. 123.

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

  124. 124.

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

  125. 125.

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

  126. 126.

    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).

  127. 127.

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

  128. 128.

    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).

  129. 129.

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

  130. 130.

    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.

  131. 131.

    , , & 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).

  132. 132.

    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.

  133. 133.

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

  134. 134.

    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.

  135. 135.

    , & MHC class II signaling in antigen-presenting cells. Curr. Opin. Immunol. 16, 108–113 (2004).

  136. 136.

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

  137. 137.

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

  138. 138.

    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.

  139. 139.

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

  140. 140.

    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).

  141. 141.

    , , , & 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).

  142. 142.

    & Therapeutic vaccination against human papilloma virus induced malignancies. Curr. Opin. Immunol. 23, 252–257 (2011).

  143. 143.

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

  144. 144.

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

  145. 145.

    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).

  146. 146.

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

  147. 147.

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

  148. 148.

    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).

  149. 149.

    , , & 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).

  150. 150.

    , , & Protein degradation and the generation of MHC class I-presented peptides. Adv. Immunol. 80, 1–70 (2002).

  151. 151.

    , & Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation. EMBO J. 26, 1385–1396 (2007).

  152. 152.

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

  153. 153.

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

  154. 154.

    , , , & 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).

  155. 155.

    , , & 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).

  156. 156.

    , , , & In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nature Immunol. 8, 101–108 (2007).

  157. 157.

    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.

  158. 158.

    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).

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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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Affiliations

  1. Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

    • Jacques Neefjes
    • , Marlieke L. M. Jongsma
    •  & Petra Paul
  2. Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, Norway.

    • Oddmund Bakke

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jacques Neefjes.

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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DOI

https://doi.org/10.1038/nri3084

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