Deconstructing the Peptide-MHC Specificity of T Cell Recognition

• Published in: Cell Vol. 157; no. 5; pp. 1073 - 1087
• Main Authors: Birnbaum, Michael E., Mendoza, Juan L., Sethi, Dhruv K., Dong, Shen, Glanville, Jacob, Dobbins, Jessica, Özkan, Engin, Davis, Mark M., Wucherpfennig, Kai W., Garcia, K. Christopher
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.05.2014
• Subjects: Algorithms; Amino Acid Sequence; Animals; Cross Reactions; High-Throughput Nucleotide Sequencing; HLA Antigens - immunology; HLA Antigens - metabolism; Humans; Ligands; Mice; Models, Molecular; Peptide Library; Peptides - chemistry; Peptides - immunology; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - chemistry; T-Lymphocytes - immunology
• DOI: 10.1016/j.cell.2014.03.047
• ISSN: 0092-8674

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. [Display omitted] •Deep sequencing peptide-MHC libraries finds hundreds of TCR-reactive peptides•TCRs exhibit limited cross-reactivity for contact residues in peptide antigens•Structures show linkages between distantly related peptide sequences•Novel strategy for identification of naturally occurring TCR ligands Combinatorial pMHC libraries mated with deep-sequencing analysis reveal that peptide antigens recognized by a given T cell receptor are surprisingly homologous and show that it is possible to predict naturally occurring peptide ligands for TCRs of interest.