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Cell. 2014 May 22;157(5):1073-87. doi: 10.1016/j.cell.2014.03.047.

Deconstructing the peptide-MHC specificity of T cell recognition.

Author information

1
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.
2
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
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.
5
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
6
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.
7
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.
8
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.

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.

PMID:
24855945
PMCID:
PMC4071348
DOI:
10.1016/j.cell.2014.03.047
[Indexed for MEDLINE]
Free PMC Article
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