Discriminating self from nonself with short peptides from large proteomes

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.

[1]  M. Huynen,et al.  The frequency distribution of gene family sizes in complete genomes. , 1998, Molecular biology and evolution.

[2]  H. Rammensee,et al.  SYFPEITHI: database for MHC ligands and peptide motifs , 1999, Immunogenetics.

[3]  Søren Brunak,et al.  Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation , 2002, Journal of Virology.

[4]  Vera van Noort,et al.  Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome , 2003, Immunogenetics.

[5]  S. Hunt,et al.  Immunobiology (5th edn.). The Immune System in Health and Disease (by CA Janeway, P Travers, M Walport and M Shlomchik) , 2002 .

[6]  S. Brunak,et al.  Prediction of proteasome cleavage motifs by neural networks. , 2002, Protein engineering.

[7]  C. Janeway,et al.  The Immune System in Health and Disease , 2001 .

[8]  M. Gerstein,et al.  Protein family and fold occurrence in genomes: power-law behaviour and evolutionary model. , 2001, Journal of molecular biology.

[9]  John Sidney,et al.  Class I molecules with similar peptide-binding specificities are the result of both common ancestry and convergent evolution , 2003, Immunogenetics.

[10]  V. Engelhard,et al.  Structure of peptides associated with class I and class II MHC molecules. , 1994, Annual review of immunology.

[11]  M. Probst-Kepper,et al.  Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. , 2000, Immunity.

[12]  T. Boon,et al.  An Antigenic Peptide Produced by Peptide Splicing in the Proteasome , 2004, Science.

[13]  G. Pesole,et al.  Compositional bias and mimicry toward the nonself proteome in immunodominant T cell epitopes of self and nonself antigens , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  J. Yewdell,et al.  Making sense of mass destruction: quantitating MHC class I antigen presentation , 2003, Nature Reviews Immunology.

[15]  P. Galanaud,et al.  Interleukin induction of non-specific suppressor cells. , 1986, Annales de l'Institut Pasteur. Immunologie.

[16]  J. Claverie,et al.  The peptidic self model: a hypothesis on the molecular nature of the immunological self. , 1986, Annales de l'Institut Pasteur. Immunology.

[17]  Jonathan W. Yewdell,et al.  Immune recognition of a human renal cancer antigen through post-translational protein splicing , 2004, Nature.

[18]  P M Kloetzel,et al.  Abrogation of CTL Epitope Processing by Single Amino Acid Substitution Flanking the C-Terminal Proteasome Cleavage Site1 , 2000, The Journal of Immunology.

[19]  K. Parker,et al.  Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. , 1994, Journal of immunology.

[20]  W Keilholz,et al.  Cleavage motifs of the yeast 20S proteasome beta subunits deduced from digests of enolase 1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. Doolittle,et al.  A kingdom-level phylogeny of eukaryotes based on combined protein data. , 2000, Science.

[22]  Andreas Meyerhans,et al.  Cytotoxic T Lymphocyte Epitopes of HIV-1 Nef , 2000, The Journal of experimental medicine.

[23]  S. Ohno.  How cytotoxic T cells manage to discriminate nonself from self at the nonapeptide level. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Sidney,et al.  Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules , 1993, Cell.

[25]  J. Borghans,et al.  Memorizing innate instructions requires a sufficiently specific adaptive immune system. , 2002, International immunology.

[26]  S Brunak,et al.  Sensitive quantitative predictions of peptide-MHC binding by a 'Query by Committee' artificial neural network approach. , 2003, Tissue antigens.

[27]  R. Mantegna,et al.  Systematic analysis of coding and noncoding DNA sequences using methods of statistical linguistics. , 1995, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[28]  P. Norman,et al.  Immunobiology: The immune system in health and disease , 1995 .

[29]  P. Matzinger.  Tolerance, danger, and the extended family. , 1994, Annual review of immunology.

[30]  R. Germain,et al.  The biochemistry and cell biology of antigen processing and presentation. , 1993, Annual review of immunology.

[31]  I Grosse,et al.  Statistical analysis of the DNA sequence of human chromosome 22. , 2001, Physical review. E, Statistical, nonlinear, and soft matter physics.

[32]  Bjoern Peters,et al.  Identifying MHC Class I Epitopes by Predicting the TAP Transport Efficiency of Epitope Precursors , 2003, The Journal of Immunology.

[33]  Jacques Neefjes,et al.  A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. , 2004, Immunity.

[34]  S. Brunak,et al.  Predicting proteasomal cleavage sites: a comparison of available methods. , 2003, International immunology.

[35]  Hans-Georg Rammensee,et al.  Two new proteases in the MHC class I processing pathway , 2000, Nature Immunology.

[36]  Charles A. Janeway,et al.  Decoding the Patterns of Self and Nonself by the Innate Immune System , 2002, Science.