# Mechanotransduction through T cell receptors: consensus, controversies and future outlooks

## TL;DR

This review explores how T cell receptors (TCRs) detect mechanical forces to initiate immune signaling and how this process helps distinguish antigens.

## Contribution

The paper synthesizes current models of TCR signal initiation and emphasizes the role of mechanical force in antigen discrimination.

## Key findings

- TCRs can act as mechanosensors, detecting mechanical forces during antigen recognition.
- Mechanical forces may modulate receptor-ligand interactions to enhance antigen discrimination.
- Comparing TCRs with other immunoreceptors reveals both shared and unique triggering mechanisms.

## Abstract

Immune cells rely on surface immunoreceptors to sense their environment. While the downstream signaling pathways of many immunoreceptors are well characterized, the initial molecular events that trigger signaling upon ligand engagement remain incompletely understood. Here, in this Review, we outline our current understanding of this immunoreceptor signal initiation problem, using the T cell antigen receptor (TCR) as a prototype. We synthesize decades of research on the TCR’s unique functional requirements and explore how these properties constrain potential triggering mechanisms. We evaluate prominent models of TCR signal initiation and highlight their respective strengths, limitations, complementary aspects and areas of ongoing debate. A central focus is the role of mechanical force in TCR triggering and antigen recognition for which we consider evidence for TCR–pMHC catch bonds, the capacity of T cells to generate endogenous forces and how these might modulate receptor–ligand kinetics and conformational changes to enhance antigen discrimination beyond classical kinetic proofreading models. By comparing TCR triggering with that of other immunoreceptors such as B cell receptors and Fc receptors, we discuss both shared principles and receptor-specific differences. This Review aims to consolidate current knowledge, reconcile conflicting findings and identify critical unanswered questions, in hopes of charting a path toward understanding how immunoreceptors convert ligand binding into cellular responses.

The immune system protects the body using various cells that communicate through receptors. This Review explores how T cell receptors (TCRs) initiate signaling, focusing on their role as mechanosensors. The authors review current knowledge and controversies about TCR signaling. TCRs are crucial for recognizing antigens and activating T cells. The study examines different models explaining how TCRs initiate signaling. These include the aggregation model, conformational change model, kinetic segregation model and mechanosensor model. Research highlights that TCRs can detect mechanical forces, which may help them distinguish between different antigens. This ability could enhance the immune response’s sensitivity and specificity. The authors suggest that understanding these mechanisms could improve therapies targeting immune responses. Future research may focus on integrating these models to fully understand TCR signaling and its implications for immune system function and potential medical applications.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.