How does the T-cell antigen receptor work?

The T-cell antigen receptor (TCR) sits at the core of adaptive immunity, yet the precise molecular mechanism by which peptide–MHC (pMHC) binding initiates intracellular signaling remains one of the most long-standing and debated questions in immunology. Despite decades of intensive work, the early triggering events that convert extracellular ligand engagement into CD3 ITAM phosphorylation are still incompletely understood. The intrinsic complexity of the multi-subunit TCR–CD3 complex, its membrane-embedded architecture, and the nature of receptor–ligand interactions have resulted in multiple mechanistic models that are often difficult to reconcile.

Recent advances in structural biology and biophysics — including cryo-EM structures of the complete TCR–CD3 complex, NMR analyses, molecular dynamics simulations, and quantitative studies of ITAM phosphorylation kinetics — coupled to genetic perturbation have provided unprecedented insight into the dynamical and energetic landscape of TCR-CD3. These developments have reinvigorated models based on allosteric regulation and the sequence of molecular events that couple pMHC recognition to the initiation of intracellular signaling.

This Research Topic aims to bring together high-quality contributions that focus strictly on the molecular and biophysical mechanisms underlying the earliest steps of TCR–CD3 triggering. We seek work that advances clarity, avoids conceptual amalgamation, and contributes to a more precise understanding of how TCR engagement is translated into signaling.

We welcome submissions addressing, but not limited to:

-Structural and biophysical analyses of the TCR–CD3 complex and TCR–pMHC interactions
-Molecular dynamics, spectroscopic, or computational and genetic perturbation studies probing conformational changes and allosteric communication within the TCR–CD3 complex
-Mechanistic models describing the initiation of CD3 ITAM phosphorylation
-TCRγδ-CD3 activation mechanism and the role of butyrophilins
-Investigations into the role of mechanical forces in ligand discrimination and signal amplification, including work on the origin of mechanical forces
-Quantitative or theoretical studies that refine, challenge, or reconcile existing models of the triggering mechanism

Prof. Gennaro De Libero holds a patent, WO2018162563