title: Deconstructing the peptide-MHC specificity of T cell recognition.
abstract: In order to survey a universe of major histocompatibility complex (MHC)-presented peptide antigens whose numbers greatly exceed the diversity of the T cell repertoire, T cell receptors (TCRs) are thought to be cross-reactive. However, the nature and extent of TCR cross-reactivity has not been conclusively measured experimentally. We developed a system to identify MHC-presented peptide ligands by combining TCR selection of highly diverse yeast-displayed peptide-MHC libraries with deep sequencing. Although we identified hundreds of peptides reactive with each of five different mouse and human TCRs, the selected peptides possessed TCR recognition motifs that bore a close resemblance to their known antigens. This structural conservation of the TCR interaction surface allowed us to exploit deep-sequencing information to computationally identify activating microbial and self-ligands for human autoimmune TCRs. The mechanistic basis of TCR cross-reactivity described here enables effective surveillance of diverse self and foreign antigens without necessitating degenerate recognition of nonhomologous peptides.
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Birnbaum
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Mendoza
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Dhruv K
authors.initials: DK
authors.lastname: Sethi
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Shen
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Glanville
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dobbins
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkan
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D003429:Cross Reactions; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011948:Receptors, Antigen, T-Cell