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EMBO J. Jun 1, 1998; 17(11): 2971–2981.
PMCID: PMC1170637

A role for HLA-DO as a co-chaperone of HLA-DM in peptide loading of MHC class II molecules.

Abstract

In B cells, the non-classical human leukocyte antigens HLA-DO (DO) and HLA-DM (DM) are residents of lysosome-like organelles where they form tight complexes. DM catalyzes the removal of invariant chain-derived CLIP peptides from classical major histocompatibility complex (MHC) class II molecules, chaperones them until peptides are available for loading, and functions as a peptide editor. Here we show that DO preferentially promotes loading of MHC class II molecules that are dependent on the chaperone activity of DM, and influences editing in a positive way for some peptides and negatively for others. In acidic compartments, DO is engaged in DR-DM-DO complexes whose physiological relevance is indicated by the observation that at lysosomal pH DM-DO stabilizes empty class II molecules more efficiently than DM alone. Moreover, expression of DO in a melanoma cell line favors loading of high-stability peptides. Thus, DO appears to act as a co-chaperone of DM, thereby controlling the quality of antigenic peptides to be presented on the cell surface.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adams TE, Bodmer JG, Bodmer WF. Production and characterization of monoclonal antibodies recognizing the alpha-chain subunits of human ia alloantigens. Immunology. 1983 Dec;50(4):613–624. [PMC free article] [PubMed]
  • Amigorena S, Webster P, Drake J, Newcomb J, Cresswell P, Mellman I. Invariant chain cleavage and peptide loading in major histocompatibility complex class II vesicles. J Exp Med. 1995 May 1;181(5):1729–1741. [PMC free article] [PubMed]
  • Avva RR, Cresswell P. In vivo and in vitro formation and dissociation of HLA-DR complexes with invariant chain-derived peptides. Immunity. 1994 Dec;1(9):763–774. [PubMed]
  • Bakke O, Dobberstein B. MHC class II-associated invariant chain contains a sorting signal for endosomal compartments. Cell. 1990 Nov 16;63(4):707–716. [PubMed]
  • Bijlmakers MJ, Benaroch P, Ploegh HL. Mapping functional regions in the lumenal domain of the class II-associated invariant chain. J Exp Med. 1994 Aug 1;180(2):623–629. [PMC free article] [PubMed]
  • Denzin LK, Cresswell P. HLA-DM induces CLIP dissociation from MHC class II alpha beta dimers and facilitates peptide loading. Cell. 1995 Jul 14;82(1):155–165. [PubMed]
  • Denzin LK, Robbins NF, Carboy-Newcomb C, Cresswell P. Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells. Immunity. 1994 Oct;1(7):595–606. [PubMed]
  • Denzin LK, Hammond C, Cresswell P. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules. J Exp Med. 1996 Dec 1;184(6):2153–2165. [PMC free article] [PubMed]
  • Denzin LK, Sant'Angelo DB, Hammond C, Surman MJ, Cresswell P. Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science. 1997 Oct 3;278(5335):106–109. [PubMed]
  • Douek DC, Altmann DM. HLA-DO is an intracellular class II molecule with distinctive thymic expression. Int Immunol. 1997 Mar;9(3):355–364. [PubMed]
  • Fling SP, Arp B, Pious D. HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells. Nature. 1994 Apr 7;368(6471):554–558. [PubMed]
  • Frydman J, Höhfeld J. Chaperones get in touch: the Hip-Hop connection. Trends Biochem Sci. 1997 Mar;22(3):87–92. [PubMed]
  • Fung-Leung WP, Surh CD, Liljedahl M, Pang J, Leturcq D, Peterson PA, Webb SR, Karlsson L. Antigen presentation and T cell development in H2-M-deficient mice. Science. 1996 Mar 1;271(5253):1278–1281. [PubMed]
  • Germain RN, Hendrix LR. MHC class II structure, occupancy and surface expression determined by post-endoplasmic reticulum antigen binding. Nature. 1991 Sep 12;353(6340):134–139. [PubMed]
  • Germain RN, Rinker AG., Jr Peptide binding inhibits protein aggregation of invariant-chain free class II dimers and promotes surface expression of occupied molecules. Nature. 1993 Jun 24;363(6431):725–728. [PubMed]
  • Katz JF, Stebbins C, Appella E, Sant AJ. Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules. J Exp Med. 1996 Nov 1;184(5):1747–1753. [PMC free article] [PubMed]
  • Kenty G, Martin WD, Van Kaer L, Bikoff EK. MHC class II expression in double mutant mice lacking invariant chain and DM functions. J Immunol. 1998 Jan 15;160(2):606–614. [PubMed]
  • Kovats S, Grubin CE, Eastman S, deRoos P, Dongre A, Van Kaer L, Rudensky AY. Invariant chain-independent function of H-2M in the formation of endogenous peptide-major histocompatibility complex class II complexes in vivo. J Exp Med. 1998 Jan 19;187(2):245–251. [PMC free article] [PubMed]
  • Kropshofer H, Bohlinger I, Max H, Kalbacher H. Self and foreign peptides interact with intact and disassembled MHC class II antigen HLA-DR via tryptophan pockets. Biochemistry. 1991 Sep 24;30(38):9177–9187. [PubMed]
  • Kropshofer H, Vogt AB, Hämmerling GJ. Structural features of the invariant chain fragment CLIP controlling rapid release from HLA-DR molecules and inhibition of peptide binding. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8313–8317. [PMC free article] [PubMed]
  • Kropshofer H, Vogt AB, Stern LJ, Hämmerling GJ. Self-release of CLIP in peptide loading of HLA-DR molecules. Science. 1995 Nov 24;270(5240):1357–1359. [PubMed]
  • Kropshofer H, Vogt AB, Moldenhauer G, Hammer J, Blum JS, Hämmerling GJ. Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J. 1996 Nov 15;15(22):6144–6154. [PMC free article] [PubMed]
  • Kropshofer H, Hämmerling GJ, Vogt AB. How HLA-DM edits the MHC class II peptide repertoire: survival of the fittest? Immunol Today. 1997 Feb;18(2):77–82. [PubMed]
  • Kropshofer H, Arndt SO, Moldenhauer G, Hämmerling GJ, Vogt AB. HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH. Immunity. 1997 Mar;6(3):293–302. [PubMed]
  • Lampson LA, Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed]
  • Liang MN, Beeson C, Mason K, McConnell HM. Kinetics of the reactions between the invariant chain (85-99) peptide and proteins of the murine class II MHC. Int Immunol. 1995 Sep;7(9):1397–1404. [PubMed]
  • Liljedahl M, Kuwana T, Fung-Leung WP, Jackson MR, Peterson PA, Karlsson L. HLA-DO is a lysosomal resident which requires association with HLA-DM for efficient intracellular transport. EMBO J. 1996 Sep 16;15(18):4817–4824. [PMC free article] [PubMed]
  • Liljedahl M, Winqvist O, Surh CD, Wong P, Ngo K, Teyton L, Peterson PA, Brunmark A, Rudensky AY, Fung-Leung WP, et al. Altered antigen presentation in mice lacking H2-O. Immunity. 1998 Feb;8(2):233–243. [PubMed]
  • Lindstedt R, Liljedahl M, Péléraux A, Peterson PA, Karlsson L. The MHC class II molecule H2-M is targeted to an endosomal compartment by a tyrosine-based targeting motif. Immunity. 1995 Nov;3(5):561–572. [PubMed]
  • Lotteau V, Teyton L, Peleraux A, Nilsson T, Karlsson L, Schmid SL, Quaranta V, Peterson PA. Intracellular transport of class II MHC molecules directed by invariant chain. Nature. 1990 Dec 13;348(6302):600–605. [PubMed]
  • Mackensen A, Ferradini L, Carcelain G, Triebel F, Faure F, Viel S, Hercend T. Evidence for in situ amplification of cytotoxic T-lymphocytes with antitumor activity in a human regressive melanoma. Cancer Res. 1993 Aug 1;53(15):3569–3573. [PubMed]
  • Marić MA, Taylor MD, Blum JS. Endosomal aspartic proteinases are required for invariant-chain processing. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2171–2175. [PMC free article] [PubMed]
  • Marks MS, Roche PA, van Donselaar E, Woodruff L, Peters PJ, Bonifacino JS. A lysosomal targeting signal in the cytoplasmic tail of the beta chain directs HLA-DM to MHC class II compartments. J Cell Biol. 1995 Oct;131(2):351–369. [PMC free article] [PubMed]
  • Martin WD, Hicks GG, Mendiratta SK, Leva HI, Ruley HE, Van Kaer L. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell. 1996 Feb 23;84(4):543–550. [PubMed]
  • Mellins E, Smith L, Arp B, Cotner T, Celis E, Pious D. Defective processing and presentation of exogenous antigens in mutants with normal HLA class II genes. Nature. 1990 Jan 4;343(6253):71–74. [PubMed]
  • Miyazaki T, Wolf P, Tourne S, Waltzinger C, Dierich A, Barois N, Ploegh H, Benoist C, Mathis D. Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway. Cell. 1996 Feb 23;84(4):531–541. [PubMed]
  • Morris P, Shaman J, Attaya M, Amaya M, Goodman S, Bergman C, Monaco JJ, Mellins E. An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules. Nature. 1994 Apr 7;368(6471):551–554. [PubMed]
  • Peters PJ, Neefjes JJ, Oorschot V, Ploegh HL, Geuze HJ. Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments. Nature. 1991 Feb 21;349(6311):669–676. [PubMed]
  • Pierre P, Denzin LK, Hammond C, Drake JR, Amigorena S, Cresswell P, Mellman I. HLA-DM is localized to conventional and unconventional MHC class II-containing endocytic compartments. Immunity. 1996 Mar;4(3):229–239. [PubMed]
  • Rammensee HG, Friede T, Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. [PubMed]
  • Riberdy JM, Newcomb JR, Surman MJ, Barbosa JA, Cresswell P. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides. Nature. 1992 Dec 3;360(6403):474–477. [PubMed]
  • Roche PA, Cresswell P. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature. 1990 Jun 14;345(6276):615–618. [PubMed]
  • Sadegh-Nasseri S, Germain RN. A role for peptide in determining MHC class II structure. Nature. 1991 Sep 12;353(6340):167–170. [PubMed]
  • Sanderson F, Kleijmeer MJ, Kelly A, Verwoerd D, Tulp A, Neefjes JJ, Geuze HJ, Trowsdale J. Accumulation of HLA-DM, a regulator of antigen presentation, in MHC class II compartments. Science. 1994 Dec 2;266(5190):1566–1569. [PubMed]
  • Sanderson F, Thomas C, Neefjes J, Trowsdale J. Association between HLA-DM and HLA-DR in vivo. Immunity. 1996 Jan;4(1):87–96. [PubMed]
  • Schafer PH, Green JM, Malapati S, Gu L, Pierce SK. HLA-DM is present in one-fifth the amount of HLA-DR in the class II peptide-loading compartment where it associates with leupeptin-induced peptide (LIP)-HLA-DR complexes. J Immunol. 1996 Dec 15;157(12):5487–5495. [PubMed]
  • Servenius B, Rask L, Peterson PA. Class II genes of the human major histocompatibility complex. The DO beta gene is a divergent member of the class II beta gene family. J Biol Chem. 1987 Jun 25;262(18):8759–8766. [PubMed]
  • Sette A, Ceman S, Kubo RT, Sakaguchi K, Appella E, Hunt DF, Davis TA, Michel H, Shabanowitz J, Rudersdorf R, et al. Invariant chain peptides in most HLA-DR molecules of an antigen-processing mutant. Science. 1992 Dec 11;258(5089):1801–1804. [PubMed]
  • Sette A, Southwood S, Miller J, Appella E. Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II. J Exp Med. 1995 Feb 1;181(2):677–683. [PMC free article] [PubMed]
  • Sherman MA, Weber DA, Jensen PE. DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity. 1995 Aug;3(2):197–205. [PubMed]
  • Sloan VS, Cameron P, Porter G, Gammon M, Amaya M, Mellins E, Zaller DM. Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature. 1995 Jun 29;375(6534):802–806. [PubMed]
  • Solheim JC, Carreno BM, Hansen TH. Are transporter associated with antigen processing (TAP) and tapasin class I MHC chaperones? J Immunol. 1997 Jan 15;158(2):541–543. [PubMed]
  • Swier K, Brown DR, Bird JJ, Martin WD, Van Kaer L, Reiner SL. A critical, invariant chain-independent role for H2-M in antigen presentation. J Immunol. 1998 Jan 15;160(2):540–544. [PubMed]
  • Takebe Y, Seiki M, Fujisawa J, Hoy P, Yokota K, Arai K, Yoshida M, Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. [PMC free article] [PubMed]
  • Tonnelle C, DeMars R, Long EO. DO beta: a new beta chain gene in HLA-D with a distinct regulation of expression. EMBO J. 1985 Nov;4(11):2839–2847. [PMC free article] [PubMed]
  • Tourne S, Miyazaki T, Wolf P, Ploegh H, Benoist C, Mathis D. Functionality of major histocompatibility complex class II molecules in mice doubly deficient for invariant chain and H-2M complexes. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9255–9260. [PMC free article] [PubMed]
  • Trowsdale J. "Both man & bird & beast": comparative organization of MHC genes. Immunogenetics. 1995;41(1):1–17. [PubMed]
  • Trowsdale J, Kelly A. The human HLA class II alpha chain gene DZ alpha is distinct from genes in the DP, DQ and DR subregions. EMBO J. 1985 Sep;4(9):2231–2237. [PMC free article] [PubMed]
  • Urban RG, Chicz RM, Strominger JL. Selective release of some invariant chain-derived peptides from HLA-DR1 molecules at endosomal pH. J Exp Med. 1994 Aug 1;180(2):751–755. [PMC free article] [PubMed]
  • van Ham SM, Grüneberg U, Malcherek G, Bröker I, Melms A, Trowsdale J. Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs. J Exp Med. 1996 Nov 1;184(5):2019–2024. [PMC free article] [PubMed]
  • van Ham SM, Tjin EP, Lillemeier BF, Grüneberg U, van Meijgaarden KE, Pastoors L, Verwoerd D, Tulp A, Canas B, Rahman D, et al. HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading. Curr Biol. 1997 Dec 1;7(12):950–957. [PubMed]
  • Vogt AB, Stern LJ, Amshoff C, Dobberstein B, Hämmerling GJ, Kropshofer H. Interference of distinct invariant chain regions with superantigen contact area and antigenic peptide binding groove of HLA-DR. J Immunol. 1995 Nov 15;155(10):4757–4765. [PubMed]
  • Vogt AB, Kropshofer H, Moldenhauer G, Hämmerling GJ. Kinetic analysis of peptide loading onto HLA-DR molecules mediated by HLA-DM. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9724–9729. [PMC free article] [PubMed]
  • Weber DA, Evavold BD, Jensen PE. Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM. Science. 1996 Oct 25;274(5287):618–620. [PubMed]

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