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.
Travaglino et al. (Thu,) studied this question.