Virtual models of the HLA class I antigen processing pathway.

Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class I binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model individual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of individual antigen processing steps, for example proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify HLA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies.

[1]  Vladimir Brusic,et al.  MHCPEP, a database of MHC-binding peptides: update 1996 , 1997, Nucleic Acids Res..

[2]  A Sette,et al.  The peptide-binding motif for the human transporter associated with antigen processing , 1995, The Journal of experimental medicine.

[3]  V Brusic,et al.  Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules. , 1998, Journal of immunology.

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

[5]  J. Yewdell,et al.  The generation of MHC class I-associated peptides is only partially inhibited by proteasome inhibitors: involvement of nonproteasomal cytosolic proteases in antigen processing? , 1997, Journal of immunology.

[6]  Ferry Ossendorp,et al.  Efficient Identification of Novel Hla-A*0201–Presented Cytotoxic T Lymphocyte Epitopes in the Widely Expressed Tumor Antigen Prame by Proteasome-Mediated Digestion Analysis , 2001, The Journal of experimental medicine.

[7]  H. Rammensee,et al.  Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products , 2001, The Journal of experimental medicine.

[8]  F. Sinigaglia,et al.  HLA class II peptide binding specificity and autoimmunity. , 1997, Advances in immunology.

[9]  J. Neefjes,et al.  Trimming of TAP-translocated peptides in the endoplasmic reticulum and in the cytosol during recycling , 1994, The Journal of experimental medicine.

[10]  Ronald N. Germain,et al.  MHC-dependent antigen processing and peptide presentation: Providing ligands for T lymphocyte activation , 1994, Cell.

[11]  J A Swets,et al.  Measuring the accuracy of diagnostic systems. , 1988, Science.

[12]  Hans-Georg Rammensee,et al.  The Human 26 S and 20 S Proteasomes Generate Overlapping but Different Sets of Peptide Fragments from a Model Protein Substrate* , 2000, The Journal of Biological Chemistry.

[13]  P. van Endert,et al.  Beyond the proteasome: trimming, degradation and generation of MHC class I ligands by auxiliary proteases. , 2002, Molecular immunology.

[14]  T. Mizushima,et al.  The structure of the mammalian 20S proteasome at 2.75 A resolution. , 2002, Structure.

[15]  K. Rock,et al.  Dissociation of β 2-microglobulin leads to the accumulation of a substantial pool of inactive class I MHC heavy chains on the cell surface , 1991, Cell.

[16]  M Nijenhuis,et al.  Identification of a contact region for peptide on the TAP1 chain of the transporter associated with antigen processing. , 1996, Journal of immunology.

[17]  J. Neefjes,et al.  Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. , 2002, Molecular immunology.

[18]  R. Henderson,et al.  HLA-A2.1-associated peptides from a mutant cell line: a second pathway of antigen presentation. , 1992, Science.

[19]  H. Margalit,et al.  Sequence signals for generation of antigenic peptides by the proteasome: implications for proteasomal cleavage mechanism. , 2000, Journal of molecular biology.

[20]  H. Rammensee,et al.  Peptides naturally presented by MHC class I molecules. , 1993, Annual review of immunology.

[21]  Eric O Long,et al.  T cell recognition of an HLA-A2-restricted epitope derived from a cleaved signal sequence , 1994, The Journal of experimental medicine.

[22]  J. Yewdell,et al.  Trimming of antigenic peptides in an early secretory compartment , 1994, The Journal of experimental medicine.

[23]  P. Kloetzel,et al.  A kinetic model of vertebrate 20S proteasome accounting for the generation of major proteolytic fragments from oligomeric peptide substrates. , 2000, Biophysical journal.

[24]  van Endert Pm.  Peptide selection for presentation by HLA class I: A role for the human transporter associated with antigen processing? , 1996 .

[25]  Vladimir Brusic,et al.  A neural network model approach to the study of human TAP transporter , 1998, Silico Biol..

[26]  P. Kloetzel,et al.  The role of the ubiquitin-proteasome pathway in MHC class I antigen processing: implications for vaccine design. , 2001, Current molecular medicine.

[27]  P. Kloetzel,et al.  The cleavage preference of the proteasome governs the yield of antigenic peptides , 1995, The Journal of experimental medicine.

[28]  S Uebel,et al.  Recognition principle of the TAP transporter disclosed by combinatorial peptide libraries. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  K. Hadeler,et al.  PAProC: a prediction algorithm for proteasomal cleavages available on the WWW , 2001, Immunogenetics.

[30]  R. Tampé,et al.  A sequential model for peptide binding and transport by the transporters associated with antigen processing. , 1994, Immunity.

[31]  B. Monsarrat,et al.  Mapping and Structural Dissection of Human 20 S Proteasome Using Proteomic Approaches* , 2002, Molecular & Cellular Proteomics.

[32]  Christina Kuttler.  An Algorithm for the Prediction of Proteasomal Cleavages , 2000, German Conference on Bioinformatics.

[33]  J. Neefjes,et al.  Peptide size selection by the major histocompatibility complex-encoded peptide transporter , 1994, The Journal of experimental medicine.

[34]  Günter J. Hämmerling,et al.  Selectivity of MHC-encoded peptide transporters from human, mouse and rat , 1994, Nature.

[35]  J. Bodmer,et al.  IMGT/HLA Database - a sequence database for the human major histocompatibility complex , 2000, Nucleic Acids Res..

[36]  Hermann-Georg Holzhütter,et al.  Assessment of proteasomal cleavage probabilities from kinetic analysis of time-dependent product formation. , 2002, Journal of molecular biology.

[37]  K Eichmann,et al.  Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. , 1995, Immunity.

[38]  D J Moss,et al.  Peptide transporter (TAP-1 and TAP-2)-independent endogenous processing of Epstein-Barr virus (EBV) latent membrane protein 2A: implications for cytotoxic T-lymphocyte control of EBV-associated malignancies , 1996, Journal of virology.

[39]  P. Kloetzel,et al.  A theoretical approach towards the identification of cleavage-determining amino acid motifs of the 20 S proteasome. , 1999, Journal of molecular biology.

[40]  Robert DeMars,et al.  Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter , 1991, Nature.

[41]  K. Smith,et al.  Peptide-dependent expression of HLA-B7 on antigen processing-deficient T2 cells. , 1996, Journal of immunology.

[42]  J. Yewdell.  Not such a dismal science: the economics of protein synthesis, folding, degradation and antigen processing. , 2001, Trends in cell biology.