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

Proceedings of the National Academy of Sciences of the United States of America
Marvin H GeeK C Garcia

Abstract

T cell receptors (TCRs) bind to peptide-major histocompatibility complex (pMHC) with low affinity (Kd ∼ μM), which is generally assumed to facilitate cross-reactive TCR "scanning" of ligands. To understand the relationship between TCR/pMHC affinity and cross-reactivity, we sought to engineer an additional weak interaction, termed "velcro," between the TCR and pMHC to probe the specificities of TCRs at relatively low and high affinities. This additional interaction was generated through an eight-amino acid peptide library covalently linked to the N terminus of the MHC-bound peptide. Velcro was selected through an affinity-based isolation and was subsequently shown to enhance the cognate TCR/pMHC affinity in a peptide-dependent manner by ∼10-fold. This was sufficient to convert a nonstimulatory ultra-low-affinity ligand into a stimulatory ligand. An X-ray crystallographic structure revealed how velcro interacts with the TCR. To probe TCR cross-reactivity, we screened TCRs against yeast-displayed pMHC libraries with and without velcro, and found that the peptide cross-reactivity profiles of low-affinity (Kd > 100 μM) and high-affinity (Kd ∼ μM) TCR/pMHC interactions are remarkably similar. The conservation of recognition of the TC...Continue Reading

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Citations

May 10, 2020·Molecular Carcinogenesis·Michele M Hoffmann, Jill E Slansky
Dec 6, 2019·MedChemComm·Sara LincianoAlessandro Angelini
Feb 13, 2020·Cellular & Molecular Immunology·Xinyi XuChenqi Xu
Nov 17, 2020·Frontiers in Immunology·Chloe H LeeHashem Koohy
Jun 29, 2021·Journal of Biomolecular Structure & Dynamics·Arne StrandJohann Deisenhofer

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