Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro

Gee, Marvin H.; Sibener, Leah V.; Birnbaum, Michael E.; Jude, Kevin M.; Yang, Xinbo; Fernandes, Ricardo A.; Mendoza, Juan L.; Glassman, Caleb R.; Garcia, K. Christopher

doi:10.1073/pnas.1802746115

Title: Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro

Journal Article · 17 July 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1802746115 · OSTI ID:1460885

Gee, Marvin H. ^[1]; Sibener, Leah V. ^[1]; Birnbaum, Michael E. ^[1]; Jude, Kevin M. ^[2]; Yang, Xinbo ^[2]; Fernandes, Ricardo A. ^[2]; Mendoza, Juan L. ^[2]; Glassman, Caleb R. ^[1]; Garcia, K. Christopher ^[3]

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305,, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305,, Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305,
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305,, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305,
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305,, Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305,, Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305,, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305

Significance T cells recognize their targets through the T cell receptor (TCR). The affinity of a typical receptor for an agonist peptide-major histocompatibility complex (pMHC) molecule is extremely weak, and TCRs are known to be cross-reactive for related peptides. However, there are known TCR/pMHC interactions that occur at weaker affinities, such as in thymic selection and recognition of self-antigens, yet little is known about the identity of these peptides. We show that TCR/pMHC interactions of extremely low affinities remain highly specific, which informs of the nature of extremely weak affinity ligands. We also show that a peptide “velcro” can induce peptide-dependent T cell activation, providing a method for increasing the potency of a target, which is useful in immunotherapy.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1460885

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 31 Vol. 115; ISSN 0027-8424

Publisher:: Proceedings of the National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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