A Brief Molecular History of Vγ9Vδ2 TCR‐Mediated Phosphoantigen Sensing DOI Creative Commons
Fiyaz Mohammed, Carrie R. Willcox, Benjamin E. Willcox

et al.

Immunological Reviews, Journal Year: 2025, Volume and Issue: 331(1)

Published: April 3, 2025

ABSTRACT Vγ9Vδ2 T‐cells are universally present in humans and represent one of the most prevalent TCR reactivities, evolutionarily conserved across diverse mammalian species. They an innate‐like subset featuring a semi‐invariant repertoire that drives their well‐recognized reactivity to small, non‐peptidic phosphoantigens (pAg). Crucially, they can distinguish between highly immunostimulatory microbially derived pAg much less potent host‐derived pAg, with former effectively acting as pathogen associated molecular pattern (PAMP) surrogate recognition receptor (PRR). Ample evidence supports important Vγ9Vδ2‐mediated contributions immunity against pathogenic bacteria parasites, mediated by effector immunoregulatory functions. The basis sensing mechanism underpinning such responses has, however, remained mysterious. Despite this, past studies have established is MHC‐independent, extremely fast, exquisitely pAg‐sensitive, dependent upon target cell expression key BTN‐family molecules, notably BTN3A BTN2A1. Here we contextualize these findings several recent addressing sensing. We integrate into single unified theory interpretable from different perspectives, both intracellular extracellular, biophysical, topological. prioritize critical questions address context this proposed model. Finally, suggest model will provide template for antigen other related γδ T‐cell subsets.

Language: Английский

Structural characterization of two γδ TCR/CD3 complexes DOI Creative Commons
Mohammed Hoque,

John Benji Grigg,

Trudy F. Ramlall

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Language: Английский

Citations

2
Biophysical and Structural Features of αβT‐Cell Receptor Mechanosensing: A Paradigmatic Shift in Understanding T‐Cell Activation DOI Creative Commons
Robert J. Mallis, Kristine N. Brazin, Jonathan S. Duke‐Cohan

et al.

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 29, 2024

ABSTRACT αβT cells protect vertebrates against many diseases, optimizing surveillance using mechanical force to distinguish between pathophysiologic cellular alterations and normal self‐constituents. The multi‐subunit αβT‐cell receptor (TCR) operates outside of thermal equilibrium, harvesting energy via physical forces generated by T‐cell motility actin‐myosin machinery. When a peptide‐bound major histocompatibility complex molecule (pMHC) on an antigen presenting cell is ligated, the αβTCR T leverages form catch bond, prolonging bond lifetime, enhancing discrimination. Under load, undergoes reversible structural transitions involving partial unfolding its clonotypic immunoglobulin‐like (Ig) domains coupled rearrangements associated CD3 subunits elements. We postulate that provide critical initiate signaling cascade induction quaternary rearrangements, membrane perturbations, exposure ITAMs phosphorylation non‐receptor tyrosine kinases, phase separation molecules. Understanding force‐mediated clarifies long‐standing questions regarding recognition, specificity affinity, providing basis for continued investigation. Future directions include examining atomistic mechanisms signal initiation, performance quality, tissue compliance adaptability, memory fate. mechanotransduction paradigm will foster improved rational design based vaccines, CAR‐Ts, adoptive therapies.

Language: Английский

Citations

3
Recognition of MR1-antigen complexes by TCR Vγ9Vδ2 DOI Creative Commons
José Pedro Loureiro, Alessandro Vacchini, Giuliano Berloffa

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 18, 2025

The TCR-mediated activation of T cells expressing the TCR Vγ9Vδ2 relies on an innate-like mechanism involving butyrophilin 3A1, 3A2 and 2A1 molecules phospho-antigens, without participation classical antigen-presenting molecules. Whether also recognize complexes composed antigens in adaptive-like manner is unknown. Here, we identify MR1-autoreactive Vγ9Vδ2. This MR1-restricted response antigen- CDR3δ-dependent butyrophilin-independent. gene transfer reconstitutes MR1-antigen recognition, engineered tetramers interact with soluble antigen-dependent manner. These are present healthy individuals low frequency mostly CD8+ or CD4-CD8 double negative. We describe a patient autoimmune symptoms γδ lymphocytosis which ~10% circulating MR1-self-reactive express release pro-inflammatory cytokines, suggesting possible disease pathogenesis. Thus, MR1-self-antigen can some TCRs Vγ9Vδ2, promoting full cell potentially contributing to diseases.

Language: Английский

Citations

0
A Brief Molecular History of Vγ9Vδ2 TCR‐Mediated Phosphoantigen Sensing DOI Creative Commons
Fiyaz Mohammed, Carrie R. Willcox, Benjamin E. Willcox

et al.

Immunological Reviews, Journal Year: 2025, Volume and Issue: 331(1)

Published: April 3, 2025

ABSTRACT Vγ9Vδ2 T‐cells are universally present in humans and represent one of the most prevalent TCR reactivities, evolutionarily conserved across diverse mammalian species. They an innate‐like subset featuring a semi‐invariant repertoire that drives their well‐recognized reactivity to small, non‐peptidic phosphoantigens (pAg). Crucially, they can distinguish between highly immunostimulatory microbially derived pAg much less potent host‐derived pAg, with former effectively acting as pathogen associated molecular pattern (PAMP) surrogate recognition receptor (PRR). Ample evidence supports important Vγ9Vδ2‐mediated contributions immunity against pathogenic bacteria parasites, mediated by effector immunoregulatory functions. The basis sensing mechanism underpinning such responses has, however, remained mysterious. Despite this, past studies have established is MHC‐independent, extremely fast, exquisitely pAg‐sensitive, dependent upon target cell expression key BTN‐family molecules, notably BTN3A BTN2A1. Here we contextualize these findings several recent addressing sensing. We integrate into single unified theory interpretable from different perspectives, both intracellular extracellular, biophysical, topological. prioritize critical questions address context this proposed model. Finally, suggest model will provide template for antigen other related γδ T‐cell subsets.

Language: Английский

Citations

0