A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes

Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1–9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a predicted pentapeptide motif as the minimal antigenic determinant presented by a class I MHC molecule and recognized by a cytolytic T lymphocyte clone

Immunoinformatics: Predicting Peptide–MHC Binding

Immunoinformatics is a discipline that applies methods of computer science to study and model the immune system. A fundamental question addressed by immunoinformatics is how to understand the rules of antigen presentation by MHC molecules to T cells, a process that is central to adaptive immune responses to infections and cancer. In the modern era of personalized medicine, the ability to model and predict which antigens can be presented by MHC is key to manipulating the immune system and designing strategies for therapeutic intervention. Since the MHC is both polygenic and extremely polymorphic, each individual possesses a personalized set of MHC molecules with different peptide-binding specificities, and collectively they present a unique individualized peptide imprint of the ongoing protein metabolism. Mapping all MHC allotypes is an enormous undertaking that cannot be achieved without a strong bioinformatics component. Computational tools for the prediction of peptide?MHC binding have thus become essential in most pipelines for T cell epitope discovery and an inescapable component of vaccine and cancer research. Here, we describe the development of several such tools, from pioneering efforts to the current state-of-the-art methods, that have allowed for accurate predictions of peptide binding of all MHC molecules, even including those that have not yet been characterized experimentally.Fil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Andreatta, Massimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Buus, Søren. Universidad de Copenhagen; Dinamarc

Reconstruction of a pathway of antigen processing and class II MHC peptide capture

Endocytosed antigens are proteolytically processed and small amounts of peptides captured by class II MHC molecules. The details of antigen proteolysis, peptide capture and how destruction of T-cell epitopes is avoided are incompletely understood. Using the tetanus toxin antigen, we show that the introduction of 3-6 cleavage sites is sufficient to trigger a partially unfolded conformation able to bind to class II MHC molecules. The known locations of T-cell epitopes and protease cleavage sites predict that large domains of processed antigen (8-35kDa) are captured under these conditions. Remarkably, when antigen is bound to the B-cell antigen receptor (BCR), processing can trigger a concerted 'hand-over' reaction whereby BCR-associated processed antigen is captured by neighbouring class II MHC molecules. Early capture of minimally processed antigen and confinement of the processing and class II MHC loading reaction to the membrane plane may improve the likelihood of T-cell epitope survival in the class II MHC pathway and may help explain the reciprocal relationships observed between B- and T-cell epitopes in many protein antigens and autoantigen