Identification of Destabilizing Residues in HLA Class II-selected Bacteriophage Display Libraries Edited by HLA-DM

European Journal of ImmunologyVolume 29, Issue 2 p. 660-668 ArticleFree Access Identification of destabilizing residues in HLA class II-selected bacteriophage display libraries edited by HLA-DM Laura Raddrizzani, Laura Raddrizzani Roche Milano Ricerche Milan, ItalySearch for more papers by this authorElisa Bono, Elisa Bono Roche Milano Ricerche Milan, ItalySearch for more papers by this authorAnne B. Vogt, Anne B. Vogt German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorHarald Kropshofer, Harald Kropshofer German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorFabio Gallazzi, Fabio Gallazzi Roche Milano Ricerche Milan, ItalySearch for more papers by this authorTiziana Sturniolo, Tiziana Sturniolo Roche Milano Ricerche Milan, ItalySearch for more papers by this authorGünter J. Hämmerling, Günter J. Hämmerling German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorFrancesco Sinigaglia, Francesco Sinigaglia Roche Milano Ricerche Milan, ItalySearch for more papers by this authorJuergen Hammer, Juergen Hammer Hoffmann-La-Roche Inc., Preclinical R&D, Nutley, USASearch for more papers by this author Laura Raddrizzani, Laura Raddrizzani Roche Milano Ricerche Milan, ItalySearch for more papers by this authorElisa Bono, Elisa Bono Roche Milano Ricerche Milan, ItalySearch for more papers by this authorAnne B. Vogt, Anne B. Vogt German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorHarald Kropshofer, Harald Kropshofer German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorFabio Gallazzi, Fabio Gallazzi Roche Milano Ricerche Milan, ItalySearch for more papers by this authorTiziana Sturniolo, Tiziana Sturniolo Roche Milano Ricerche Milan, ItalySearch for more papers by this authorGünter J. Hämmerling, Günter J. Hämmerling German Cancer Research Center, Department of Molecular Immunology, Heidelberg, GermanySearch for more papers by this authorFrancesco Sinigaglia, Francesco Sinigaglia Roche Milano Ricerche Milan, ItalySearch for more papers by this authorJuergen Hammer, Juergen Hammer Hoffmann-La-Roche Inc., Preclinical R&D, Nutley, USASearch for more papers by this author First published: 28 March 2006 https://doi.org/10.1002/(SICI)1521-4141(199902)29:02<660::AID-IMMU660>3.0.CO;2-ICitations: 26AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract HLA-DM (DM) functions as a peptide editor by catalyzing the release of class II-associated invariant chain peptides (CLIP) and other unstable peptides, thus supporting the formation of stable class II-peptide complexes for presentation. To investigate the general features that determine the DM susceptibility of HLA-DR1/peptide complexes, we generated a large DM-ensitive peptide repertoire from an M13 bacteriophage display library using a novel double selection protocol: we selected bacteriophage capable of binding to DR1 molecules and, subsequently, we enriched DR1-bound bacteriophage susceptible to elution by purified DM molecules. Sequence and mutational analyses of the DR1/DM double-selected peptides revealed that the amino acids Gly and Pro play a destabilizing role in the dissociation kinetics of DR1 ligands. This observation was confirmed also in natural peptide sequences such as CLIP 89 – 101, HA 307 – 319 and bovine collagen II (CII) 261–273. Our results demonstrate that DM susceptibility does not only depend on the number and nature of anchor residues, or the peptide length. Instead, less obvious sequence characteristics play a major role in the DM editing process and ultimately in the composition of peptide repertoires presented to T cells. Reference 1 Germain, R. N., MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994. 76: 287– 299. 2 Busch, R. and Mellins, E. D., Developing and shedding inhibitions: how MHC class II molecules reach maturity. Curr. Opin. Immunol. 1996, 8: 51– 58. 3 Kropshofer, H., Hammerling, G. J. and Vogt, A. B., How HLA-DM edits the MHC class II peptide repertoire: survival of the fittest? Immunol. Today 1997. 18: 77– 82. 4 Roche, P. A., HLA-DM: An in vivo facilitator of MHC class II peptide loading. Immunity 1995. 3: 259– 262. 5 Kropshofer, H., Arndt, S. O., Moldenhauer, G., Hammerling, G. J. and Vogt, A. B., HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH. Immunity 1997. 6: 293– 302. 6 Lightstone, L., Hargreaves, R., Bobek, G., Peterson, M., Aichinger, G., Lombard, G. and Lechler, R., In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM. Proc. Natl. Acad. Sci. USA 1997. 94: 5772– 5777. 7 Tourne, S., Miyazaki, T., Wolf, P., Ploegh, H., Benoist, C. and 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. USA 1997. 94: 9255– 9260. 8 Katz, J. F., Stebbins, C., Appella, E. and Sant, A. J., Invariant chain and DM edit self peptide presentation by major histocompatibility complex (MHC) class II molecules. J. Exp. Med. 1996. 184: 1747– 1753. 9 Kropshofer, H., Vogt, A. B., Moldenhauer, G., Hammer, J., Blum, J. S. and Hämmerling, G. J., Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J. 1996. 15: 6144– 6154. 10 Weber, D. A., Evavold, B. D. and Jensen, P. E., Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM. Science 1996. 274: 618– 620. 11 van Ham, S. M., Gruneberg, U., Malcherek, G., Broker, I., Melms, A. and Trowsdale, J., Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs. J. Exp. Med. 1996. 184: 2019– 2024. 12 Vogt, A. B., Kropshofer, H., Moldenhauer, G. and Hämmerling, G. J., Kinetic analysis of peptide loading onto HLA-DR molecules mediated by HLA-DM. Proc. Natl. Acad. Sci. USA 1996. 93: 9724– 9729. 13 Sloan, V. S., Cameron, P., Porter, G., Gammon, M., Amaya, M., Mellins, E. and Zaller, D. M., Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature 1995. 375: 802– 806. 14 Denzin, L. K. and Cresswell, P., HLA-DM induces CLIP dissociation from MHC class II αβ dimers and facilitates peptide loading. Cell 1995. 82: 155– 165. 15 Sherman, M. A., Weber, D. A. and Jensen, P. E., DM enhances peptide binding to class II MHC by release of invariant chain-derived peptide. Immunity 1995. 3: 197– 205. 16 Denzin, L. K., Hammond, C. and Cresswell, P., HLADM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules. J. Exp. Med. 1996. 184: 2153– 2165. 17 Sanderson, F., Thomas, C., Neefjes, J. and Trowsdale, J., Association between HLA-DM and HLA-DR in vivo. Immunity 1996. 4: 87– 96. 18 Hammer, J. and Sinigaglia, F., in I. Lefkovits (Ed.), Immunology Methods Manual: The Comprehensive Sourcebook of Techniques, Academic Press, Ltd., London 1997, p. 625– 635. 19 Hammer, J., Valsasnini, P., Tolba, K., Bolin, D., Higelin, J., Takacs, B. and Sinigaglia, F., Promiscuous and allele-specific anchors in HLA-DR binding peptides. Cell 1993. 74: 197– 203. 20 Hammer, J., Takacs, B. and Sinigaglia, F., Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J. Exp. Med. 1992. 176: 1007– 1013. 21 Hammer, J., Belunis, C., Bolin, D., Papadopoulos, J., Walsky, R., Higelin, J., Danho, W., Sinigaglia, F. and Nagy, Z. A., High-affinity binding of short peptides to major histocompatibility complex class II molecules by anchor combinations. Proc. Natl. Acad. Sci. USA 1994. 91: 4456– 4460. 22 Hammer, J., Sturniolo, T. and Sinigaglia, F., HLA class II peptide binding specificity and autoimmunity. Adv. Immunol. 1997. 66: 67– 100. 23 Chou, P. Y. and Fasman, G. D., Conformational parameters for amino acids in helical, β-sheet, and random coil regions calculated from proteins. Biochemistry 1974. 13: 211– 222. 24 Fugger, L., Rothbard, J. B. and Sonderstrup-McDevitt, G., Specificity of an HLA-DRB1+0401-restricted T cell response to type II collagen. Eur. J. Immunol. 1996. 26: 928– 933. 25 Rosloniec, E. F., Brand, D. D., Myers, L. K., Whittington, K. B., Gumanovskaya, M., Zaller, D. M., Woods, A., Altmann, D. M., Stuart, J. M. and Kang, A. H., An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen. J. Exp. Med. 1997. 185: 1113– 1122. 26 Stern, L. J., Brown, J. H., Jardetzky, T. S., Gorga, J. C., Urban, R. G., Strominger, J. L. and Wiley, D. C., Crystal structure of the human class II MHC protein HLA-DR1 complexed with an Influenza virus peptide. Nature 1994. 368: 215– 221. 27 Lindner, R. and Unanue, E. R., Distinct antigen MHC class II complexes generated by separate processing pathways. EMBO J. 1996. 15: 6910– 6920. 28 Ma, C. and Blum, J. S., Receptor-mediated endocytosis of antigens overcomes the requirement for HLA-DM in class II-restricted antigen presentation. J. Immunol. 1997. 158: 1– 4. 29 Vergelli, M., Pinet, V., Vogt, A. B., Kalbus, M., Malnati, M., Riccio, P., Long, E. O. and Martin, R., HLA-DR-restricted presentation of purified myelin basic protein is independent of intracellular processing. Eur. J. Immunol. 1997. 27: 941– 951. 30 Kropshofer, H., Vogt, A. B., Thery, C., Armandola, E. A., Li, B.-C., Moldenhauer, G., Amigorena, S. and Hammerling, G. J., A role for HLA-DO as a cochaperone of HLA-DM in peptide loading of MHC class II molecules. EMBO J. 1998. 17: 2971– 2981. 31 van Ham, S. M., Tjin, E. P. M., Lillemeier, B. F., Gruneberg, U., van Meijgaarden, K. E., Pastoors, L., Verwoerd, D., Tulp, A., Canas, B., Rahman, D., Ottenhoff, T. H. M., Pappin, D. J. C., Trowsdale, J. and Neefjes, J., HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading. Curr. Biol. 1997. 7: 950– 957. 32 Sinigaglia, F., Romagnoli, P., Guttinger, M., Takacs, B. and Pink, J. R. L., Selection of Tcell epitopes and vaccine engineering. Methods Enzymol. 1992. 203: 370– 386. 33 Cammarota, G., Scheirle, A., Takacs, B., Doran, D. M., Knorr, R., Bannwarth, W., Guardiola, J. and Sinigaglia, F., Identification of a CD4 binding site on the β2 domain of HLA-DR molecules. Nature 1992. 356: 799– 801. 34 Denzin, L. K., Robbins, N. F., Carboy-Newcomb, C. and Cresswell, P., Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells. Immunity 1994. 1: 595– 606. 35 Raddrizzani, L., Sturniolo, T., Guenot, J., Bono, E., Gallazzi, F., Nagy, Z. A., Sinigaglia, F. and Hammer, J., Different modes of peptide interaction enable HLA-DQ and HLA-DR molecules to bind diverse peptide repertoires. J. Immunol. 1997. 159: 703– 711. 36 Brown, J. H., Jardetzky, T. S., Gorga, J. C., Stern, L. J., Urban, R. G., Strominger, J. L. and Wiley, D. C., The three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 1993. 364: 33– 39. Citing Literature Volume29, Issue2February 1999Pages 660-668 ReferencesRelatedInformation