1932

Abstract

MHC class II (MHC-II) molecules are critical in the control of many immune responses. They are also involved in most autoimmune diseases and other pathologies. Here, we describe the biology of MHC-II and MHC-II variations that affect immune responses. We discuss the classic cell biology of MHC-II and various perturbations. Proteolysis is a major process in the biology of MHC-II, and we describe the various components forming and controlling this endosomal proteolytic machinery. This process ultimately determines the MHC-II–presented peptidome, including cryptic peptides, modified peptides, and other peptides that are relevant in autoimmune responses. MHC-II also variable in expression, glycosylation, and turnover. We illustrate that MHC-II is variable not only in amino acids (polymorphic) but also in its biology, with consequences for both health and disease.

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2016-05-20
2024-04-27
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Literature Cited

  1. Neefjes J, Jongsma ML, Paul P, Bakke O. 1.  2011. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 11:823–36 [Google Scholar]
  2. Kambayashi T, Laufer TM. 2.  2014. Atypical MHC class II–expressing antigen-presenting cells: Can anything replace a dendritic cell?. Nat. Rev. Immunol. 14:719–30 [Google Scholar]
  3. Kared H, Camous X, Larbi A. 3.  2014. T cells and their cytokines in persistent stimulation of the immune system. Curr. Opin. Immunol. 29:79–85 [Google Scholar]
  4. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P. 4.  et al. 2008. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLOS Genet. 4:e1000024 [Google Scholar]
  5. Dilthey A, Cox C, Iqbal Z, Nelson MR, McVean G. 5.  2015. Improved genome inference in the MHC using a population reference graph. Nat. Genet. 47:682–88 [Google Scholar]
  6. Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG. 6.  et al. 1994. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368:215–21 [Google Scholar]
  7. Beck S, Trowsdale J. 7.  2000. The human major histocompatability complex: lessons from the DNA sequence. Annu. Rev. Genom. Hum. Genet. 1:117–37 [Google Scholar]
  8. Jardetzky TS, Brown JH, Gorga JC, Stern LJ, Urban RG. 8.  et al. 1996. Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II–like conformation for bound peptides. PNAS 93:734–38 [Google Scholar]
  9. Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG. 9.  1994. Pool sequencing of natural HLA-DR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules. Immunogenetics 39:230–42 [Google Scholar]
  10. Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. 10.  2015. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33:169–200 [Google Scholar]
  11. Castellino F, Zappacosta F, Coligan JE, Germain RN. 11.  1998. Large protein fragments as substrates for endocytic antigen capture by MHC class II molecules. J. Immunol. 161:4048–57 [Google Scholar]
  12. Sercarz EE, Maverakis E. 12.  2003. MHC-guided processing: binding of large antigen fragments. Nat. Rev. Immunol. 3:621–29 [Google Scholar]
  13. Zhang P, Leu JI, Murphy ME, George DL, Marmorstein R. 13.  2014. Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLOS ONE 9:e103518 [Google Scholar]
  14. Hughes AL. 14.  2002. Natural selection and the diversification of vertebrate immune effectors. Immunol. Rev. 190:161–68 [Google Scholar]
  15. Trowsdale J, Parham P. 15.  2004. Mini-review: defense strategies and immunity-related genes. Eur. J. Immunol. 34:7–17 [Google Scholar]
  16. Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ. 16.  et al. 2007. Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. PNAS 104:16221–26 [Google Scholar]
  17. Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK. 17.  et al. 2012. Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell 151:1557–68 [Google Scholar]
  18. Boog CJ, Neefjes JJ, Boes J, Ploegh HL, Melief CJ. 18.  1989. Specific immune responses restored by alteration in carbohydrate chains of surface molecules on antigen-presenting cells. Eur. J. Immunol. 19:537–42 [Google Scholar]
  19. Bolscher JG, van der Bijl MM, Neefjes JJ, Hall A, Smets LA, Ploegh HL. 19.  1988. Ras (proto)oncogene induces N-linked carbohydrate modification: temporal relationship with induction of invasive potential. EMBO J. 7:3361–68 [Google Scholar]
  20. Neefjes JJ, De Bruijn ML, Boog CJ, Nieland JD, Boes J. 20.  et al. 1990. N-linked glycan modification on antigen-presenting cells restores an allospecific cytotoxic T cell response. J. Exp. Med. 171:583–88 [Google Scholar]
  21. Blum JS, Wearsch PA, Cresswell P. 21.  2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443–73 [Google Scholar]
  22. Roche PA, Marks MS, Cresswell P. 22.  1991. Formation of a nine-subunit complex by HLA class II glycoproteins and the invariant chain. Nature 354:392–94 [Google Scholar]
  23. Romagnoli P, Germain RN. 23.  1994. The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy. J. Exp. Med. 180:1107–13 [Google Scholar]
  24. Roche PA, Cresswell P. 24.  1991. Proteolysis of the class II–associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. PNAS 88:3150–54 [Google Scholar]
  25. Zhong G, Castellino F, Romagnoli P, Germain RN. 25.  1996. Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II–associated invariant chain peptides (CLIP). J. Exp. Med. 184:2061–66 [Google Scholar]
  26. Neefjes JJ, Stollorz V, Peters PJ, Geuze HJ, Ploegh HL. 26.  1990. The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route. Cell 61:171–83 [Google Scholar]
  27. Peters PJ, Neefjes JJ, Oorschot V, Ploegh HL, Geuze HJ. 27.  1991. Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments. Nature 349:669–76 [Google Scholar]
  28. Bakke O, Dobberstein B. 28.  1990. MHC class II–associated invariant chain contains a sorting signal for endosomal compartments. Cell 63:707–16 [Google Scholar]
  29. Bikoff EK, Huang LY, Episkopou V, van Meerwijk J, Germain RN, Robertson EJ. 29.  1993. Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J. Exp. Med. 177:1699–712 [Google Scholar]
  30. Viville S, Neefjes J, Lotteau V, Dierich A, Lemeur M. 30.  et al. 1993. Mice lacking the MHC class II–associated invariant chain. Cell 72:635–48 [Google Scholar]
  31. Villadangos JA, Bryant RA, Deussing J, Driessen C, Lennon-Dumenil AM. 31.  et al. 1999. Proteases involved in MHC class II antigen presentation. Immunol. Rev. 172:109–20 [Google Scholar]
  32. Bergmann H, Yabas M, Short A, Miosge L, Barthel N. 32.  et al. 2013. B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8 dendritic cells require the intramembrane endopeptidase SPPL2A. J. Exp. Med. 210:31–40 [Google Scholar]
  33. Beisner DR, Langerak P, Parker AE, Dahlberg C, Otero FJ. 33.  et al. 2013. The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J. Exp. Med. 210:23–30 [Google Scholar]
  34. Neefjes JJ, Ploegh HL. 34.  1992. Inhibition of endosomal proteolytic activity by leupeptin blocks surface expression of MHC class II molecules and their conversion to SDS resistance αβ heterodimers in endosomes. EMBO J. 11:411–16 [Google Scholar]
  35. Ghosh P, Amaya M, Mellins E, Wiley DC. 35.  1995. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Nature 378:457–62 [Google Scholar]
  36. Anders AK, Call MJ, Schulze MS, Fowler KD, Schubert DA. 36.  et al. 2011. HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide. Nat. Immunol. 12:54–61 [Google Scholar]
  37. Sherman MA, Weber DA, Jensen PE. 37.  1995. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 3:197–205 [Google Scholar]
  38. Mosyak L, Zaller DM, Wiley DC. 38.  1998. The structure of HLA-DM, the peptide exchange catalyst that loads antigen onto class II MHC molecules during antigen presentation. Immunity 9:377–83 [Google Scholar]
  39. Fremont DH, Crawford F, Marrack P, Hendrickson WA, Kappler J. 39.  1998. Crystal structure of mouse H2-M. Immunity 9:385–93 [Google Scholar]
  40. Doebele RC, Pashine A, Liu W, Zaller DM, Belmares M. 40.  et al. 2003. Point mutations in or near the antigen-binding groove of HLA-DR3 implicate class II–associated invariant chain peptide affinity as a constraint on MHC class II polymorphism. J. Immunol. 170:4683–92 [Google Scholar]
  41. Kropshofer H, Vogt AB, Moldenhauer G, Hammer J, Blum JS, Hammerling GJ. 41.  1996. Editing of the HLA-DR–peptide repertoire by HLA-DM. EMBO J. 15:6144–54 [Google Scholar]
  42. Denzin LK, Cresswell P. 42.  1995. HLA-DM induces CLIP dissociation from MHC class II αβ dimers and facilitates peptide loading. Cell 82:155–65 [Google Scholar]
  43. Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. 43.  1997. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388:782–87 [Google Scholar]
  44. Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J. 44.  et al. 1997. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388:787–92 [Google Scholar]
  45. Martin WD, Hicks GG, Mendiratta SK, Leva HI, Ruley HE, Van Kaer L. 45.  1996. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell 84:543–50 [Google Scholar]
  46. Chapman DC, Williams DB. 46.  2010. ER quality control in the biogenesis of MHC class I molecules. Semin. Cell Dev. Biol. 21:512–19 [Google Scholar]
  47. Marks MS, Roche PA, van Donselaar E, Woodruff L, Peters PJ, Bonifacino JS. 47.  1995. A lysosomal targeting signal in the cytoplasmic tail of the β chain directs HLA-DM to MHC class II compartments. J. Cell Biol. 131:351–69 [Google Scholar]
  48. De Gassart A, Camosseto V, Thibodeau J, Ceppi M, Catalan N. 48.  et al. 2008. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. PNAS 105:3491–96 [Google Scholar]
  49. Shin JS, Ebersold M, Pypaert M, Delamarre L, Hartley A, Mellman I. 49.  2006. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444:115–18 [Google Scholar]
  50. Boname JM, Lehner PJ. 50.  2011. What has the study of the K3 and K5 viral ubiquitin E3 ligases taught us about ubiquitin-mediated receptor regulation?. Viruses 3:118–31 [Google Scholar]
  51. Lapaque N, Hutchinson JL, Jones DC, Meresse S, Holden DW. 51.  et al. 2009. Salmonella regulates polyubiquitination and surface expression of MHC class II antigens. PNAS 106:14052–57 [Google Scholar]
  52. Matsuki Y, Ohmura-Hoshino M, Goto E, Aoki M, Mito-Yoshida M. 52.  et al. 2007. Novel regulation of MHC class II function in B cells. EMBO J. 26:846–54 [Google Scholar]
  53. Cho KJ, Walseng E, Ishido S, Roche PA. 53.  2015. Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells. PNAS 112:10449–54 [Google Scholar]
  54. van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA. 54.  et al. 2006. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25:885–94 [Google Scholar]
  55. Amigorena S, Drake JR, Webster P, Mellman I. 55.  1994. Transient accumulation of new class II MHC molecules in a novel endocytic compartment in B lymphocytes. Nature 369:113–20 [Google Scholar]
  56. Neefjes J. 56.  1999. CIIV, MIIC and other compartments for MHC class II loading. Eur. J. Immunol. 29:1421–25 [Google Scholar]
  57. Allen PM, Unanue ER. 57.  1984. Differential requirements for antigen processing by macrophages for lysozyme-specific T cell hybridomas. J. Immunol. 132:1077–79 [Google Scholar]
  58. Pierre P, Denzin LK, Hammond C, Drake JR, Amigorena S. 58.  et al. 1996. HLA-DM is localized to conventional and unconventional MHC class II–containing endocytic compartments. Immunity 4:229–39 [Google Scholar]
  59. Li M, Rong Y, Chuang YS, Peng D, Emr SD. 59.  2015. Ubiquitin-dependent lysosomal membrane protein sorting and degradation. Mol. Cell 57:467–78 [Google Scholar]
  60. Sanderson F, Kleijmeer MJ, Kelly A, Verwoerd D, Tulp A. 60.  et al. 1994. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science 266:1566–69 [Google Scholar]
  61. Hammond C, Denzin LK, Pan M, Griffith JM, Geuze HJ, Cresswell P. 61.  1998. The tetraspan protein CD82 is a resident of MHC class II compartments where it associates with HLA-DR, -DM, and -DO molecules. J. Immunol. 161:3282–91 [Google Scholar]
  62. Hoorn T, Paul P, Janssen L, Janssen H, Neefjes J. 62.  2012. Dynamics within tetraspanin pairs affect MHC class II expression. J. Cell Sci. 125:328–39 [Google Scholar]
  63. Segura E, Guerin C, Hogg N, Amigorena S, Thery C. 63.  2007. CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J. Immunol. 179:1489–96 [Google Scholar]
  64. Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J. 64.  et al. 2005. Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape. Immunity 22:221–33 [Google Scholar]
  65. Arunachalam B, Phan UT, Geuze HJ, Cresswell P. 65.  2000. Enzymatic reduction of disulfide bonds in lysosomes: characterization of a γ-interferon–inducible lysosomal thiol reductase (GILT). PNAS 97:745–50 [Google Scholar]
  66. Fernandez-Borja M, Verwoerd D, Sanderson F, Aerts H, Trowsdale J. 66.  et al. 1996. HLA-DM and MHC class II molecules co-distribute with peptidase-containing lysosomal subcompartments. Int. Immunol. 8:625–40 [Google Scholar]
  67. Bosch B, Berger AC, Khandelwal S, Heipertz EL, Scharf B. 67.  et al. 2013. Disruption of multivesicular body vesicles does not affect major histocompatibility complex (MHC) class II–peptide complex formation and antigen presentation by dendritic cells. J. Biol. Chem. 288:24286–92 [Google Scholar]
  68. Moss CX, Villadangos JA, Watts C. 68.  2005. Destructive potential of the aspartyl protease cathepsin D in MHC class II–restricted antigen processing. Eur. J. Immunol. 35:3442–51 [Google Scholar]
  69. Shi GP, Villadangos JA, Dranoff G, Small C, Gu L. 69.  et al. 1999. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10:197–206 [Google Scholar]
  70. Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N. 70.  et al. 1999. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity 10:207–17 [Google Scholar]
  71. Tolosa E, Li W, Yasuda Y, Wienhold W, Denzin LK. 71.  et al. 2003. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J. Clin. Investig. 112:517–26 [Google Scholar]
  72. Yamamoto K, Kawakubo T, Yasukochi A, Tsukuba T. 72.  2012. Emerging roles of cathepsin E in host defense mechanisms. Biochim. Biophys. Acta 1824:105–12 [Google Scholar]
  73. Rossi A, Deveraux Q, Turk B, Sali A. 73.  2004. Comprehensive search for cysteine cathepsins in the human genome. Biol. Chem. 385:363–72 [Google Scholar]
  74. Heng TS, Painter MW. 74.  2008. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9:1091–94 [Google Scholar]
  75. Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. 75.  2005. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307:1630–34 [Google Scholar]
  76. McCurley N, Mellman I. 76.  2010. Monocyte-derived dendritic cells exhibit increased levels of lysosomal proteolysis as compared to other human dendritic cell populations. PLOS ONE 5:e11949 [Google Scholar]
  77. Musil D, Zucic D, Turk D, Engh RA, Mayr I. 77.  et al. 1991. The refined 2.15 Å X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. EMBO J. 10:2321–30 [Google Scholar]
  78. Turk D, Janjic V, Stern I, Podobnik M, Lamba D. 78.  et al. 2001. Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J. 20:6570–82 [Google Scholar]
  79. Turk D, Guncar G. 79.  2003. Lysosomal cysteine proteases (cathepsins): promising drug targets. Acta Crystallogr. D 59:203–13 [Google Scholar]
  80. Nagler DK, Zhang R, Tam W, Sulea T, Purisima EO, Menard R. 80.  1999. Human cathepsin X: a cysteine protease with unique carboxypeptidase activity. Biochemistry 38:12648–54 [Google Scholar]
  81. Groves MR, Coulombe R, Jenkins J, Cygler M. 81.  1998. Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes. Proteins 32:504–14 [Google Scholar]
  82. Jerala R, Zerovnik E, Kidric J, Turk V. 82.  1998. pH-induced conformational transitions of the propeptide of human cathepsin L: a role for a molten globule state in zymogen activation. J. Biol. Chem. 273:11498–504 [Google Scholar]
  83. Pierre P, Mellman I. 83.  1998. Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell 93:1135–45 [Google Scholar]
  84. Abrahamson M, Alvarez-Fernandez M, Nathanson CM. 84.  2003. Cystatins. Biochem. Soc. Symp. 2003:179–99 [Google Scholar]
  85. Turk V, Stoka V, Turk D. 85.  2008. Cystatins: biochemical and structural properties, and medical relevance. Front. Biosci. 13:5406–20 [Google Scholar]
  86. Hall A, Hakansson K, Mason RW, Grubb A, Abrahamson M. 86.  1995. Structural basis for the biological specificity of cystatin C: identification of leucine 9 in the N-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases. J. Biol. Chem. 270:5115–21 [Google Scholar]
  87. El-Sukkari D, Wilson NS, Hakansson K, Steptoe RJ, Grubb A. 87.  et al. 2003. The protease inhibitor cystatin C is differentially expressed among dendritic cell populations, but does not control antigen presentation. J. Immunol. 171:5003–11 [Google Scholar]
  88. Salvesen G, Parkes C, Abrahamson M, Grubb A, Barrett AJ. 88.  1986. Human low-Mr kininogen contains three copies of a cystatin sequence that are divergent in structure and in inhibitory activity for cysteine proteinases. Biochem. J. 234:429–34 [Google Scholar]
  89. Turk B, Stoka V, Turk V, Johansson G, Cazzulo JJ, Bjork I. 89.  1996. High-molecular-weight kininogen binds two molecules of cysteine proteinases with different rate constants. FEBS Lett. 391:109–12 [Google Scholar]
  90. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T. 90.  et al. 2012. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim. Biophys. Acta 1824:68–88 [Google Scholar]
  91. Wiener JJ, Sun S, Thurmond RL. 91.  2010. Recent advances in the design of cathepsin S inhibitors. Curr. Top. Med. Chem. 10:717–32 [Google Scholar]
  92. Saegusa K, Ishimaru N, Yanagi K, Arakaki R, Ogawa K. 92.  et al. 2002. Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J. Clin. Investig. 110:361–69 [Google Scholar]
  93. Rupanagudi KV, Kulkarni OP, Lichtnekert J, Darisipudi MN, Mulay SR. 93.  et al. 2015. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II–mediated CD4 T cell and B cell priming. Ann. Rheum. Dis. 74:452–63 [Google Scholar]
  94. Bevec T, Stoka V, Pungercic G, Dolenc I, Turk V. 94.  1996. Major histocompatibility complex class II–associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. J. Exp. Med. 183:1331–38 [Google Scholar]
  95. Mihelic M, Dobersek A, Guncar G, Turk D. 95.  2008. Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation. J. Biol. Chem. 283:14453–60 [Google Scholar]
  96. Shachar I, Elliott EA, Chasnoff B, Grewal IS, Flavell RA. 96.  1995. Reconstitution of invariant chain function in transgenic mice in vivo by individual p31 and p41 isoforms. Immunity 3:373–83 [Google Scholar]
  97. Schuttelkopf AW, Hamilton G, Watts C, van Aalten DM. 97.  2006. Structural basis of reduction-dependent activation of human cystatin F. J. Biol. Chem. 281:16570–75 [Google Scholar]
  98. Alvarez-Fernandez M, Liang YH, Abrahamson M, Su XD. 98.  2005. Crystal structure of human cystatin D, a cysteine peptidase inhibitor with restricted inhibition profile. J. Biol. Chem. 280:18221–28 [Google Scholar]
  99. Janowski R, Kozak M, Jankowska E, Grzonka Z, Grubb A. 99.  et al. 2001. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat. Struct. Biol. 8:316–20 [Google Scholar]
  100. Jenko S, Dolenc I, Guncar G, Dobersek A, Podobnik M, Turk D. 100.  2003. Crystal structure of stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo- and exopeptidases. J. Mol. Biol. 326:875–85 [Google Scholar]
  101. Guncar G, Pungercic G, Klemencic I, Turk V, Turk D. 101.  1999. Crystal structure of MHC class II–associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S. EMBO J. 18:793–803 [Google Scholar]
  102. Bode W, Engh R, Musil D, Thiele U, Huber R. 102.  et al. 1988. The 2.0 Å X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J. 7:2593–99 [Google Scholar]
  103. Stubbs MT, Laber B, Bode W, Huber R, Jerala R. 103.  et al. 1990. The refined 2.4 Å X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: a novel type of proteinase inhibitor interaction. EMBO J. 9:1939–47 [Google Scholar]
  104. Wubbolts R, Fernandez-Borja M, Oomen L, Verwoerd D, Janssen H. 104.  et al. 1996. Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J. Cell Biol. 135:611–22 [Google Scholar]
  105. Kleijmeer M, Ramm G, Schuurhuis D, Griffith J, Rescigno M. 105.  et al. 2001. Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells. J. Cell Biol. 155:53–63 [Google Scholar]
  106. Boes M, Cerny J, Massol R, Op den Brouw M, Kirchhausen T. 106.  et al. 2002. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418:983–88 [Google Scholar]
  107. Wubbolts R, Fernandez-Borja M, Jordens I, Reits E, Dusseljee S. 107.  et al. 1999. Opposing motor activities of dynein and kinesin determine retention and transport of MHC class II–containing compartments. J. Cell Sci. 112:Pt. 6785–95 [Google Scholar]
  108. Roche PA, Furuta K. 108.  2015. The ins and outs of MHC class II–mediated antigen processing and presentation. Nat. Rev. Immunol. 15:203–16 [Google Scholar]
  109. Rocha N, Neefjes J. 109.  2008. MHC class II molecules on the move for successful antigen presentation. EMBO J. 27:1–5 [Google Scholar]
  110. Paul P, van den Hoorn T, Jongsma ML, Bakker MJ, Hengeveld R. 110.  et al. 2011. A genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell 145:268–83 [Google Scholar]
  111. Michelet X, Garg S, Wolf BJ, Tuli A, Ricciardi-Castagnoli P, Brenner MB. 111.  2015. MHC class II presentation is controlled by the lysosomal small GTPase, Arl8b. J. Immunol. 194:2079–88 [Google Scholar]
  112. van der Kant R, Fish A, Janssen L, Janssen H, Krom S. 112.  et al. 2013. Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L. J. Cell Sci. 126:3462–74 [Google Scholar]
  113. Rocha N, Kuijl C, van der Kant R, Janssen L, Houben D. 113.  et al. 2009. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150Glued and late endosome positioning. J. Cell Biol. 185:1209–25 [Google Scholar]
  114. Deretic V, Saitoh T, Akira S. 114.  2013. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13:722–37 [Google Scholar]
  115. Strawbridge AB, Blum JS. 115.  2007. Autophagy in MHC class II antigen processing. Curr. Opin. Immunol. 19:87–92 [Google Scholar]
  116. Schmid D, Pypaert M, Munz C. 116.  2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26:79–92 [Google Scholar]
  117. Suri A, Walters JJ, Rohrs HW, Gross ML, Unanue ER. 117.  2008. First signature of islet β-cell–derived naturally processed peptides selected by diabetogenic class II MHC molecules. J. Immunol. 180:3849–56 [Google Scholar]
  118. Dongre AR, Kovats S, deRoos P, McCormack AL, Nakagawa T. 118.  et al. 2001. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31:1485–94 [Google Scholar]
  119. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M. 119.  et al. 2005. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. PNAS 102:7922–27 [Google Scholar]
  120. Chicz RM, Urban RG, Gorga JC, Vignali DA, Lane WS, Strominger JL. 120.  1993. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J. Exp. Med. 178:27–47 [Google Scholar]
  121. Lich JD, Elliott JF, Blum JS. 121.  2000. Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. J. Exp. Med. 191:1513–24 [Google Scholar]
  122. Jaraquemada D, Marti M, Long EO. 122.  1990. An endogenous processing pathway in vaccinia virus–infected cells for presentation of cytoplasmic antigens to class II–restricted T cells. J. Exp. Med. 172:947–54 [Google Scholar]
  123. Bonifaz LC, Arzate S, Moreno J. 123.  1999. Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. Eur. J. Immunol. 29:119–31 [Google Scholar]
  124. Malnati MS, Marti M, LaVaute T, Jaraquemada D, Biddison W. 124.  et al. 1992. Processing pathways for presentation of cytosolic antigen to MHC class II–restricted T cells. Nature 357:702–4 [Google Scholar]
  125. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D. 125.  et al. 2005. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–96 [Google Scholar]
  126. Ireland JM, Unanue ER. 126.  2011. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med. 208:2625–32 [Google Scholar]
  127. Vossenaar ER, van Venrooij WJ. 127.  2004. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res. Ther. 6:107–11 [Google Scholar]
  128. Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L. 128.  2008. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26:651–75 [Google Scholar]
  129. Ireland J, Herzog J, Unanue ER. 129.  2006. Cutting edge: Unique T cells that recognize citrullinated peptides are a feature of protein immunization. J. Immunol. 177:1421–25 [Google Scholar]
  130. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. 130.  2004. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15:1101–11 [Google Scholar]
  131. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. 131.  2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:396–400 [Google Scholar]
  132. Aichinger M, Wu C, Nedjic J, Klein L. 132.  2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210:287–300 [Google Scholar]
  133. Munz C. 133.  2015. Of LAP, CUPS, and DRibbles—unconventional use of autophagy proteins for MHC restricted antigen presentation. Front. Immunol. 6:200 [Google Scholar]
  134. Mehta P, Henault J, Kolbeck R, Sanjuan MA. 134.  2014. Noncanonical autophagy: one small step for LC3, one giant leap for immunity. Curr. Opin. Immunol. 26:69–75 [Google Scholar]
  135. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F. 135.  et al. 2007. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–57 [Google Scholar]
  136. Romao S, Gasser N, Becker AC, Guhl B, Bajagic M. 136.  et al. 2013. Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J. Cell Biol. 203:757–66 [Google Scholar]
  137. Huang J, Brumell JH. 137.  2014. Bacteria-autophagy interplay: a battle for survival. Nat. Rev. Microbiol. 12:101–14 [Google Scholar]
  138. Florey O, Kim SE, Sandoval CP, Haynes CM, Overholtzer M. 138.  2011. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat. Cell Biol. 13:1335–43 [Google Scholar]
  139. Ma J, Becker C, Lowell CA, Underhill DM. 139.  2012. Dectin-1–triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens. J. Biol. Chem. 287:34149–56 [Google Scholar]
  140. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH. 140.  et al. 2010. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity 32:227–39 [Google Scholar]
  141. Reith W, LeibundGut-Landmann S, Waldburger JM. 141.  2005. Regulation of MHC class II gene expression by the class II transactivator. Nat. Rev. Immunol. 5:793–806 [Google Scholar]
  142. Wright KL, Ting JP. 142.  2006. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol. 27:405–12 [Google Scholar]
  143. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F. 143.  et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 [Google Scholar]
  144. Samie M, Cresswell P. 144.  2015. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen–presentation pathways. Nat. Immunol. 16:729–36 [Google Scholar]
  145. Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R. 145.  1997. Interleukin-10 down-regulates MHC class II αβ peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7:861–71 [Google Scholar]
  146. Kuipers HF, Biesta PJ, Groothuis TA, Neefjes JJ, Mommaas AM, van den Elsen PJ. 146.  2005. Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains. Hum. Immunol. 66:653–65 [Google Scholar]
  147. Watts C, Lanzavecchia A. 147.  1993. Suppressive effect of antibody on processing of T cell epitopes. J. Exp. Med. 178:1459–63 [Google Scholar]
  148. Simitsek PD, Campbell DG, Lanzavecchia A, Fairweather N, Watts C. 148.  1995. Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J. Exp. Med. 181:1957–63 [Google Scholar]
  149. Ziegler HK, Unanue ER. 149.  1982. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. PNAS 79:175–78 [Google Scholar]
  150. Chesnut RW, Colon SM, Grey HM. 150.  1982. Requirements for the processing of antigens by antigen-presenting B cells. I. Functional comparison of B cell tumors and macrophages. J. Immunol. 129:2382–88 [Google Scholar]
  151. Allen PM, Strydom DJ, Unanue ER. 151.  1984. Processing of lysozyme by macrophages: identification of the determinant recognized by two T-cell hybridomas. PNAS 81:2489–93 [Google Scholar]
  152. Shimonkevitz R, Colon S, Kappler JW, Marrack P, Grey HM. 152.  1984. Antigen recognition by H-2–restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J. Immunol. 133:2067–74 [Google Scholar]
  153. Ziegler K, Unanue ER. 153.  1981. Identification of a macrophage antigen-processing event required for I-region–restricted antigen presentation to T lymphocytes. J. Immunol. 127:1869–75 [Google Scholar]
  154. Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M. 154.  et al. 1997. HLA-DR–restricted presentation of purified myelin basic protein is independent of intracellular processing. Eur. J. Immunol. 27:941–51 [Google Scholar]
  155. Lindner R, Unanue ER. 155.  1996. Distinct antigen MHC class II complexes generated by separate processing pathways. EMBO J. 15:6910–20 [Google Scholar]
  156. Lee P, Matsueda GR, Allen PM. 156.  1988. T cell recognition of fibrinogen: A determinant on the A α-chain does not require processing. J. Immunol. 140:1063–68 [Google Scholar]
  157. Donermeyer DL, Allen PM. 157.  1989. Binding to Ia protects an immunogenic peptide from proteolytic degradation. J. Immunol. 142:1063–68 [Google Scholar]
  158. Carrasco-Marin E, Petzold S, Unanue ER. 158.  1999. Two structural states of complexes of peptide and class II major histocompatibility complex revealed by photoaffinity-labeled peptides. J. Biol. Chem. 274:31333–40 [Google Scholar]
  159. Cabaniols JP, Cibotti R, Kourilsky P, Kosmatopoulos K, Kanellopoulos JM. 159.  1994. Dose-dependent T cell tolerance to an immunodominant self peptide. Eur. J. Immunol. 24:1743–49 [Google Scholar]
  160. Gammon G, Sercarz E. 160.  1989. How some T cells escape tolerance induction. Nature 342:183–85 [Google Scholar]
  161. Barlow AK, He X, Janeway C Jr. 161.  1998. Exogenously provided peptides of a self-antigen can be processed into forms that are recognized by self-T cells. J. Exp. Med. 187:1403–15 [Google Scholar]
  162. Lovitch SB, Walters JJ, Gross ML, Unanue ER. 162.  2003. APCs present Aβk-derived peptides that are autoantigenic to type B T cells. J. Immunol. 170:4155–60 [Google Scholar]
  163. Viner NJ, Nelson CA, Deck B, Unanue ER. 163.  1996. Complexes generated by the binding of free peptides to class II MHC molecules are antigenically diverse compared with those generated by intracellular processing. J. Immunol. 156:2365–68 [Google Scholar]
  164. Pu Z, Carrero JA, Unanue ER. 164.  2002. Distinct recognition by two subsets of T cells of an MHC class II–peptide complex. PNAS 99:8844–49 [Google Scholar]
  165. Pu Z, Lovitch SB, Bikoff EK, Unanue ER. 165.  2004. T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM. Immunity 20:467–76 [Google Scholar]
  166. Weigle WO. 166.  1965. The induction of autoimmunity in rabbits following injection of heterologous or altered homologous thyroglobulin. J. Exp. Med. 121:289–308 [Google Scholar]
  167. McCluskey RT, Miller F, Benacerraf B. 167.  1962. Sensitization to denatured autologous γ globulin. J. Exp. Med. 115:253–73 [Google Scholar]
  168. Rosenthal AS, Barcinski MA, Blake JT. 168.  1977. Determinant selection is a macrophage dependent immune response gene function. Nature 267:156–58 [Google Scholar]
  169. Thomas JW, George-Gattner H, Danho W. 169.  1989. T cells recognize both conformational and cryptic determinants on the insulin molecule. Eur. J. Immunol. 19:557–58 [Google Scholar]
  170. Peterson DA, DiPaolo RJ, Kanagawa O, Unanue ER. 170.  1999. Quantitative analysis of the T cell repertoire that escapes negative selection. Immunity 11:453–62 [Google Scholar]
  171. Wegmann DR, Norbury-Glaser M, Daniel D. 171.  1994. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur. J. Immunol. 24:1853–57 [Google Scholar]
  172. Daniel D, Gill RG, Schloot N, Wegmann D. 172.  1995. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol. 25:1056–62 [Google Scholar]
  173. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. 173.  2010. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat. Immunol. 11:350–54 [Google Scholar]
  174. Mohan JF, Petzold SJ, Unanue ER. 174.  2011. Register shifting of an insulin peptide–MHC complex allows diabetogenic T cells to escape thymic deletion. J. Exp. Med. 208:2375–83 [Google Scholar]
  175. Unanue ER. 175.  2014. Antigen presentation in the autoimmune diabetes of the NOD mouse. Annu. Rev. Immunol. 32:579–608 [Google Scholar]
  176. Anderton SM. 176.  2004. Post-translational modifications of self antigens: implications for autoimmunity. Curr. Opin. Immunol. 16:753–58 [Google Scholar]
  177. Petersen J, Purcell AW, Rossjohn J. 177.  2009. Post-translationally modified T cell epitopes: immune recognition and immunotherapy. J. Mol. Med. 87:1045–51 [Google Scholar]
  178. Birnboim HC, Lemay AM, Lam DK, Goldstein R, Webb JR. 178.  2003. Cutting edge: MHC class II–restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response. J. Immunol. 171:528–32 [Google Scholar]
  179. Herzog J, Maekawa Y, Cirrito TP, Illian BS, Unanue ER. 179.  2005. Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells. PNAS 102:7928–33 [Google Scholar]
  180. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. 180.  2003. Cutting edge: The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis–associated HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171:538–41 [Google Scholar]
  181. Koning F, Thomas R, Rossjohn J, Toes RE. 181.  2015. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat. Rev. Rheumatol. 11:450–61 [Google Scholar]
  182. Gregersen PK, Goyert SM, Song QL, Silver J. 182.  1987. Microheterogeneity of HLA-DR4 haplotypes: DNA sequence analysis of LD“KT2” and LD“TAS” haplotypes. Hum. Immunol. 19:287–92 [Google Scholar]
  183. Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ. 183.  et al. 2013. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210:2569–82 [Google Scholar]
  184. Cordova KN, Willis VC, Haskins K, Holers VM. 184.  2013. A citrullinated fibrinogen–specific T cell line enhances autoimmune arthritis in a mouse model of rheumatoid arthritis. J. Immunol. 190:1457–65 [Google Scholar]
  185. James EA, Rieck M, Pieper J, Gebe JA, Yue BB. 185.  et al. 2014. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66:1712–22 [Google Scholar]
  186. Backlund J, Carlsen S, Hoger T, Holm B, Fugger L. 186.  et al. 2002. Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis. PNAS 99:9960–65 [Google Scholar]
  187. Cao L, Sun D, Whitaker JN. 187.  1998. Citrullinated myelin basic protein induces experimental autoimmune encephalomyelitis in Lewis rats through a diverse T cell repertoire. J. Neuroimmunol. 88:21–29 [Google Scholar]
  188. Moscarello MA, Mastronardi FG, Wood DD. 188.  2007. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 32:251–56 [Google Scholar]
  189. Rose NR. 189.  2011. The genetics of autoimmune thyroiditis: the first decade. J. Autoimmun. 37:88–94 [Google Scholar]
  190. Braley-Mullen H, Yu S. 190.  2015. NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and Sjogren's syndrome. Adv. Immunol. 126:1–43 [Google Scholar]
  191. Kolypetri P, Carayanniotis K, Rahman S, Georghiou PE, Magafa V. 191.  et al. 2014. The thyroxine-containing thyroglobulin peptide (aa 2549–2560) is a target epitope in iodide-accelerated spontaneous autoimmune thyroiditis. J. Immunol. 193:96–101 [Google Scholar]
  192. Sollid LM, Jabri B. 192.  2011. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr. Opin. Immunol. 23:732–38 [Google Scholar]
  193. Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM. 193.  2009. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat. Immunol. 10:1096–101 [Google Scholar]
  194. Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S. 194.  et al. 2008. The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456:534–38 [Google Scholar]
  195. Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C. 195.  et al. 1998. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4:713–17 [Google Scholar]
  196. Qiao SW, Bergseng E, Molberg O, Jung G, Fleckenstein B, Sollid LM. 196.  2005. Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J. Immunol. 175:254–61 [Google Scholar]
  197. Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA. 197.  et al. 2010. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Transl. Med. 2:41ra51 [Google Scholar]
  198. Petersen J, Montserrat V, Mujico JR, Loh KL, Beringer DX. 198.  et al. 2014. T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat. Struct. Mol. Biol. 21:480–88 [Google Scholar]
  199. Jones VE, Leskowitz S. 199.  1965. Role of the carrier in development of delayed sensitivity to the azophenyl-arsonate group. Nature 207:596–97 [Google Scholar]
  200. Thomas DW. 200.  1978. Hapten-specific T lymphocyte activation by glutaraldehyde-treated macrophages: an argument against antigen processing by macrophages. J. Immunol. 121:1760–66 [Google Scholar]
  201. Falta MT, Pinilla C, Mack DG, Tinega AN, Crawford F. 201.  et al. 2013. Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. J. Exp. Med. 210:1403–18 [Google Scholar]
  202. Fontenot AP, Keizer TS, McCleskey M, Mack DG, Meza-Romero R. 202.  et al. 2006. Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells. J. Immunol. 177:3874–83 [Google Scholar]
  203. Bill JR, Mack DG, Falta MT, Maier LA, Sullivan AK. 203.  et al. 2005. Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II β-chain. J. Immunol. 175:7029–37 [Google Scholar]
  204. Clayton GM, Wang Y, Crawford F, Novikov A, Wimberly BT. 204.  et al. 2014. Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132–42 [Google Scholar]
  205. Wang Y, Dai S. 205.  2013. Structural basis of metal hypersensitivity. Immunol. Res. 55:83–90 [Google Scholar]
  206. Kalish RS, Johnson KL. 206.  1990. Enrichment and function of urushiol (poison ivy)-specific T lymphocytes in lesions of allergic contact dermatitis to urushiol. J. Immunol. 145:3706–13 [Google Scholar]
  207. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z. 207.  et al. 2012. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486:554–58 [Google Scholar]
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