PREreviews of “T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands” | PREreview

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T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands

by Johannes Pettmann, Enas Abu-Shah, Mikhail Kutuzov, Daniel B. Wilson, Michael L. Dustin, Simon J. Davis, P. Anton van der Merwe, and Omer Dushek

Posted: November 15, 2020
Server: bioRxiv
DOI: 10.1101/2020.11.14.382630

Abstract

T cells use their T cell receptors (TCRs) to discriminate between peptide MHC (pMHC) ligands that bind with different affinities but precisely how different remains controversial. This is partly because the affinities of physiologically relevant interactions are often too weak to measure. Here, we introduce a surface plasmon resonance protocol to measure ultra-low TCR/pMHC affinities (K_D~ 1000μM). Using naïve, memory, and blasted human CD8⁺T cells we find that their discrimination power is unexpectedly low, in that they require a large >100-fold decrease in affinity to abolish responses. Interestingly, the discrimination power reduces further when antigen is presented in isolation on artificial surfaces but can be partially restored by adding ligands to CD2 or LFA-1. We were able to fit the kinetic proof-reading model to our data, yielding the first estimates for both the time delay (2.8 s) and number of biochemical steps (2.67). The fractional number of steps suggest that one of the proof-reading steps is not easily reversible.

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by Zaki Molvi

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1 PREreview

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PREreview by Zaki Molvi

Authored by Zaki Molvi

Summary
Pettman et al. present a commendable approach to a pressing enigma in T cell immunology: how does a T cell receptor (TCR) differentiate between its target and off-targets? The authors developed an SPR method to measure TCR affinity for off-target peptide-MHC complexes that interact with…

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