Parsing Digital or Analog TCR Performance Through Piconewton Forces

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Aug 14

PMID 39141734

Authors

Aoi Akitsu

Eiji Kobayashi

Yinnian Feng

Hannah M Stephens

Kristine N Brazin

Daniel J Masi

Evan H Kirkpatrick

Robert J Mallis

Jonathan S Duke-Cohan

Matthew A Booker

Vincenzo Cinella

William W Feng

Elizabeth L Holliday

Jonathan J Lee

Katarzyna J Zienkiewicz

Michael Y Tolstorukov

Wonmuk Hwang

Matthew J Lang

Ellis L Reinherz

Affiliations

Soon will be listed here.

Abstract

αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP/D and PA/D, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.

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