Skip to main content

Advertisement

SpringerLink
Log in

Discriminating self from nonself with short peptides from large proteomes

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

We studied whether the peptides of nine amino acids (9-mers) that are typically used in MHC class I presentation are sufficiently unique for self:nonself discrimination. The human proteome contains 28,783 proteins, comprising 107 distinct 9-mers. Enumerating distinct 9-mers for a variety of microorganisms we found that the average overlap, i.e., the probability that a foreign peptide also occurs in the human self, is about 0.2%. This self:nonself overlap increased when shorter peptides were used, e.g., was 30% for 6-mers and 3% for 7-mers. Predicting all 9-mers that are expected to be cleaved by the immunoproteasome and to be translocated by TAP, we find that about 25% of the self and the nonself 9-mers are processed successfully. For the HLA-A*0201 and HLA-A*0204 alleles, we predicted which of the processed 9-mers from each proteome are expected to be presented on the MHC. Both alleles prefer to present processed 9-mers to nonprocessed 9-mers, and both have small preference to present foreign peptides. Because a number of amino acids from each 9-mer bind the MHC, and are therefore not exposed to the TCR, antigen presentation seems to involve a significant loss of information. Our results show that this is not the case because the HLA molecules are fairly specific. Removing the two anchor residues from each presented peptide, we find that the self:nonself overlap of these exposed 7-mers resembles that of 9-mers. Summarizing, the 9-mers used in MHC class I presentation tend to carry sufficient information to detect nonself peptides amongst self peptides.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–C
Fig. 2A, B

Similar content being viewed by others

References

  • Baldauf SL, Roger AJ, WenkSiefert I, Doolittle WF (2000) A kingdom-level phylogeny of eukaryotes based on combined protein data. Science 290:972–977

    Article  CAS  PubMed  Google Scholar 

  • Beekman NJ, Van Veelen PA, Van Hall T, Neisig A, Sijts A, Camps M, Kloetzel PM, Neefjes JJ, Melief C J, Ossendorp F (2000) Abrogation of CTL epitope processing by single amino acid substitution flanking the C-terminal proteasome cleavage site. J Immunol 164:1898–1905

    CAS  PubMed  Google Scholar 

  • Borghans JA, De Boer RJ (2002) Memorizing innate instructions requires a sufficiently specific adaptive immune system. Int Immunol 14:525–532

    Article  CAS  PubMed  Google Scholar 

  • Buus S, Lauemoller SL, Worning P, Kesmir C, Frimurer T, Corbet S, Fomsgaard A, Hilden J, Holm A, Brunak S (2003) Sensitive quantitative predictions of peptide-MHC binding by a ‘Query by Committee’ artificial neural network approach. Tissue Antigens 62:378–384

    Article  CAS  PubMed  Google Scholar 

  • Engelhard VH (1994) Structure of peptides associated with class I and class II MHC molecules. Annu Rev Immunol 12:181–207

    Article  CAS  PubMed  Google Scholar 

  • Germain RN, Margulies DH (1993) The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 11:403–450

    Article  CAS  PubMed  Google Scholar 

  • Hanada K, Yewdell JW, Yang JC (2004) Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427:252–256

    Article  CAS  PubMed  Google Scholar 

  • Holste D, Grosse I, Herzel H (2001) Statistical analysis of the DNA sequence of human chromosome 22. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 64:41917

    Article  CAS  Google Scholar 

  • Huynen MA, Van Nimwegen E (1998) The frequency distribution of gene family sizes in complete genomes. Mol Biol Evol 15:583–589

    CAS  PubMed  Google Scholar 

  • Janeway CA, Travers P, Walport M, Shlomchik M (2001) Immunobiology. The immune system in health and disease, 5th edn. Garland, New York

  • Kesmir C, Nussbaum AK, Schild H, Detours V, Brunak S (2002) Prediction of proteasome cleavage motifs by neural networks. Protein Eng 15:287–296

    Article  CAS  PubMed  Google Scholar 

  • Kesmir C, Van Noort V, De Boer RJ, Hogeweg P (2003) Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome. Immunogenetics 55:437–449

    Article  CAS  PubMed  Google Scholar 

  • Kourilsky P, Claverie JM (1986) The peptidic self model: a hypothesis on the molecular nature of the immunological self. Ann Inst Pasteur Immunol 137:3–21

    Google Scholar 

  • Lucchiari-Hartz M, Van Endert PM, Lauvau G, Maier R, Meyerhans A, Mann D, Eichmann K, Niedermann G (2000) Cytotoxic T lymphocyte epitopes of HIVNef: generation of multiple definitive major histocompatibility complex class I ligands by proteasomes. J Exp Med 191:239–252

    Article  CAS  PubMed  Google Scholar 

  • Mantegna RN, Buldyrev SV, Goldberger AL, Havlin S, Peng CK, Simons M, Stanley HE (1995) Systematic analysis of coding and noncoding DNA sequences using methods of statistical linguistics. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 52:2939–2950

    Article  CAS  PubMed  Google Scholar 

  • Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045

    CAS  PubMed  Google Scholar 

  • Medzhitov R, Janeway Jr CA (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300

    Article  CAS  PubMed  Google Scholar 

  • Morel S, Levy F, BurletSchiltz O, Brasseur F, ProbstKepper M, Peitrequin AL, Monsarrat B, Van Velthoven R, Cerottini JC, Boon T, Gairin JE, Van den Eynde BJ (2000) Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity 12:107–117

    Article  CAS  PubMed  Google Scholar 

  • Nussbaum AK, Dick TP, Keilholz W, Schirle M, Stevanovic S, Dietz K, Heinemeyer W, Groll M, Wolf DH, Huber R, Rammensee HG, Schild H (1998) Cleavage motifs of the yeast 20S proteasome β subunits deduced from digests of enolase 1. Proc Natl Acad Sci USA 95:12504–12509

    Article  CAS  PubMed  Google Scholar 

  • Ohno S (1992) How cytotoxic T cells manage to discriminate nonself from self at the nonapeptide level. Proc Natl Acad Sci USA 89:4643–4647

    CAS  PubMed  Google Scholar 

  • Parker KC, Bednarek MA, Coligan JE (1994) Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide sidechains. J Immunol 152:163–175

    CAS  PubMed  Google Scholar 

  • Peters B, Bulik S, Tampe R, Van Endert PM, Holzhutter HG (2003) Identifying MHC class I epitopes by predicting the TAP transport efficiency of epitope precursors. J Immunol 171:1741–1749

    CAS  PubMed  Google Scholar 

  • Qian J, Luscombe NM, Gerstein M (2001) Protein family and fold occurrence in genomes: power-law behaviour and evolutionary model. J Mol Biol 313:673–681

    Article  CAS  PubMed  Google Scholar 

  • Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219

    Article  CAS  PubMed  Google Scholar 

  • Reits E, Neijssen J, Herberts C, Benckhuijsen W, Janssen L, Drijfhout JW, Neefjes J (2004) A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20:495–506

    Article  CAS  PubMed  Google Scholar 

  • Ristori G, Salvetti M, Pesole G, Attimonelli M, Buttinelli C, Martin R, Riccio P (2000) Compositional bias and mimicry toward the nonself proteome in immunodominant T-cell epitopes of self and nonself antigens. FASEB J 14:431–438

    CAS  PubMed  Google Scholar 

  • Ruppert J, Sidney J, Celis E, Kubo RT, Grey M, Sette A (1993) Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell 74:929–937

    Article  CAS  PubMed  Google Scholar 

  • Saxova P, Buus S, Brunak S, Kesmir C (2003) Predicting proteasomal cleavage sites: a comparison of available methods. Int Immunol 15:781–787

    Article  CAS  PubMed  Google Scholar 

  • Sette A, Sidney J, Livingston BD, Dzuris JL, Crimi C, Walker CM, Southwood S, Collins EJ, Hughes AL (2003) Class I molecules with similar peptide binding specificities are the result of both common ancestry and convergent evolution. Immunogenetics 54:830–841

    CAS  PubMed  Google Scholar 

  • Stoltze L, Schirle M, Schwarz G, Schroter C, Thompson MW, Hersh L B, Kalbacher H, Stevanovic S, Rammensee HG, Schild H (2000) Two new proteases in the MHC class I processing pathway. Nat Immunol 1:413–418

    Article  CAS  PubMed  Google Scholar 

  • Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, Van Der Bruggen P, Boon T, Van Den Eynde BJ (2004) An antigenic peptide produced by peptide splicing in the proteasome. Science 304:587–590

    Article  CAS  PubMed  Google Scholar 

  • Yewdell JW, Reits E, Neefjes J (2003) Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat Rev Immunol 3:952–961

    Article  CAS  PubMed  Google Scholar 

  • Yusim K, Kesmir C, Gaschen B, Addo MM, Altfeld M, Brunak S, Chigaev A, Detours V, Korber BT (2002) Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV) proteins reveal imprints of immune evasion on HIV global variation. J Virol 76:8757–8768

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the valuable input of Hugo van den Berg, José Borghans, Vera van Noort, and Paulien Hogeweg. C.K. was supported by the Bioinformatic Program of Netherlands organization for scientific research (NWO, 050.50.202).

Author information

Authors and Affiliations

  1. Mathematics Institute, University of Warwick, Coventry, UK

    Nigel J. Burroughs

  2. Theoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands

    Rob J. de Boer & Can Keşmir

  3. Center for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark, Lyngby, Denmark

    Can Keşmir

Authors
  1. Nigel J. Burroughs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rob J. de Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Can Keşmir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Can Keşmir.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burroughs, N.J., de Boer, R.J. & Keşmir, C. Discriminating self from nonself with short peptides from large proteomes. Immunogenetics 56, 311–320 (2004). https://doi.org/10.1007/s00251-004-0691-0

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-004-0691-0

Keywords

Search

Navigation