title: A population response analysis approach to assign class II HLA-epitope restrictions.
abstract: Identification of the specific HLA locus and allele presenting an epitope for recognition by specific TCRs (HLA restriction) is necessary to fully characterize the immune response to Ags. Experimental determination of HLA restriction is complex and technically challenging. As an alternative, the restricting HLA locus and allele can be inferred by genetic association, using response data in an HLA-typed population. However, simple odds ratio (OR) calculations can be problematic when dealing with large numbers of subjects and Ags, and because the same epitope can be presented by multiple alleles (epitope promiscuity). In this study, we develop a tool, denominated Restrictor Analysis Tool for Epitopes, to extract inferred restriction from HLA class II-typed epitope responses. This automated method infers HLA class II restriction from large datasets of T cell responses in HLA class II-typed subjects by calculating ORs and relative frequencies from simple data tables. The program is validated by: 1) analyzing data of previously determined HLA restrictions; 2) experimentally determining in selected individuals new HLA restrictions using HLA-transfected cell lines; and 3) predicting HLA restriction of particular peptides and showing that corresponding HLA class II tetramers efficiently bind to epitope-specific T cells. We further design a specific iterative algorithm to account for promiscuous recognition by calculation of OR values for combinations of different HLA molecules while incorporating predicted HLA binding affinity. The Restrictor Analysis Tool for Epitopes program streamlines the prediction of HLA class II restriction across multiple T cell epitopes and HLA types.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Myles B C
authors.initials: MBC
authors.lastname: Dillon
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Cecilia S Lindestam
authors.initials: CSL
authors.lastname: Arlehamn
authors.affiliation: The Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305.
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.affiliation: The Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Denise M
authors.initials: DM
authors.lastname: McKinney
authors.affiliation: Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Thomas Jens
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000465:Algorithms; D000483:Alleles; D019295:Computational Biology / Q000379:methods; D066264:Datasets as Topic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006650:Histocompatibility Testing; D006801:Humans; D020407:Internet; D018448:Models, Immunological; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D012984:Software; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011948:Receptors, Antigen, T-Cell