Abstract
In vertebrates, the major histocompatibility complex (MHC) presents peptides to the immune system. In humans, MHCs are called human leukocyte antigens (HLAs), and some of the loci encoding them are the most polymorphic in the human genome. Different MHC molecules present different subsets of peptides, and knowledge of their binding specificities is important for understanding the differences in the immune response between individuals. Knowledge of motifs may be used to identify epitopes, to understand the MHC restriction of epitopes, and to compare the specificities of different MHC molecules. Algorithms that predict which peptides MHC molecules bind have recently been developed and cover many different alleles, but the utility of these algorithms is hampered by the lack of tools for browsing and comparing the specificity of these molecules. We have, therefore, developed a web server, MHC motif viewer, that allows the display of the likely binding motif for all human class I proteins of the loci HLA A, B, C, and E and for MHC class I molecules from chimpanzee (Pan troglodytes), rhesus monkey (Macaca mulatta), and mouse (Mus musculus). Furthermore, it covers all HLA-DR protein sequences. A special viewing feature, MHC fight, allows for display of the specificity of two different MHC molecules side by side. We show how the web server can be used to discover and display surprising similarities as well as differences between MHC molecules within and between different species. The MHC motif viewer is available at http://www.cbs.dtu.dk/biotools/MHCMotifViewer/.
This is a preview of subscription content, log in via an institution to check access.
References
Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W et al (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402. doi:10.1093/nar/25.17.3389
Ellis SA, Bontrop RE, Antczak DF, Ballingall K, Davies CJ, Kaufman J et al (2006) ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005. Immunogenetics 57:953–958. doi:10.1007/s00251-005-0071-4
Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351:290–296. doi:10.1038/351290a0
Frahm N, Yusim K, Suscovich TJ, Adams S, Sidney J, Hraber P et al (2007) Extensive HLA class I allele promiscuity among viral CTL epitopes. Eur J Immunol 37:2419–2433. doi:10.1002/eji.200737365
Hoof I, Kesmir C, Lund O, Nielsen M (2008) Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection. AIDS 22:1299–1303
Jacob L, Vert JP (2008) Efficient peptide-MHC-I binding prediction for alleles with few known binders. Bioinformatics 24:358–366. doi:10.1093/bioinformatics/btm611
Jojic N, Reyes-Gomez M, Heckerman D, Kadie C, Schueler-Furman O (2006) Learning MHC I–peptide binding. Bioinformatics 22:227–e235. doi:10.1093/bioinformatics/btl255
Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P et al (2004) Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 55:797–810. doi:10.1007/s00251-004-0647-4
Nielsen M, Lundegaard C, Worning P, Lauemoller SL, Lamberth K, Buus S et al (2003) Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci 12:1007–1017. doi:10.1110/ps.0239403
Nielsen M, Lundegaard C, Worning P, Hvid CS, Lamberth K, Buus S et al (2004) Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach. Bioinformatics 20:1388–1397. doi:10.1093/bioinformatics/bth100
Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S et al (2007) NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One 2:796. doi:10.1371/journal.pone.0000796
Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S et al (2008) Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLOS Comput Biol 4(7):e1000107
Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219. doi:10.1007/s002510050595
Robinson J, Waller MJ, Parham P, Bodmer JG, Marsh SGE (2001) IMGT/HLA Database - a sequence database for the human major histocompatibility complex. Nucleic Acids Res 29:210–213. doi:10.1093/nar/29.1.210
Schneider TD, Stephens RM (1990) Sequence logos: a new way to display consensus sequences. Nucleic Acids Res 18:6097–6100. doi:10.1093/nar/18.20.6097
Sette A, Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and –B polymorphism. Immunogenetics 50:201–212. doi:10.1007/s002510050594
Sette A, Fleri W, Peters B, Sathiamurthy M, Bui HH, Wilson S (2005a) A roadmap for the immunomics of category A-C pathogens. Immunity 22:155–161. doi:10.1016/j.immuni.2005.01.009
Sette A, Sidney J, Bui HH, del Guercio MF, Alexander J, Loffredo J et al (2005b) Characterization of the peptide-binding specificity of Mamu-A*11 results in the identification of SIV-derived epitopes and interspecies cross-reactivity. Immunogenetics 57:53–68. doi:10.1007/s00251-004-0749-z
Sidney J, Asabe S, Peters B, Purton KA, Chung J, Pencille TJ et al (2006) Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics 58:559–570. doi:10.1007/s00251-006-0131-4
Thompson CB (1995) New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3:531–539. doi:10.1016/1074-7613(95)90124-8
Yewdell JW, Bennink JR (1999) Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu Rev Immunol 17:51–88. doi:10.1146/annurev.immunol.17.1.51
Acknowledgements
This work was supported by the EC contract FP6-2004-IST-4, No.028069 (ImmunoGrid) and NIAID Contracts no. HHSN266200400083C and HHSN26620040006C