A Brief Molecular History of Vγ9Vδ2 TCR ‐Mediated Phosphoantigen Sensing

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