An Update on the Molecular Basis of Phosphoantigen Recognition by Vγ9Vδ2 T Cells

About 1-5% of human blood T cells are V gamma 9V delta 2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose gamma-chains contain a rearrangement of V gamma 9 with JP (TRGV9JPor V gamma 2J gamma 1.2) and are paired with V delta 2 (TRDV2)-containing delta-chains. These TCRs respond to phosphoantigens (PAg) such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is found in many pathogens, and isopentenyl pyrophosphate (IPP), which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. Until recently, these cells were believed to be restricted to primates, while no such cells are found in rodents. The identification of three genes pivotal for PAg recognition encoding for V gamma 9, V delta 2, and butyrophilin (BTN) 3 in various non-primate species identified candidate species possessing PAg-reactive V gamma 9V delta 2 T cells. Here, we review the current knowledge of the molecular basis of PAg recognition. This not only includes human V gamma 9V delta 2 T cells and the recent discovery of BTN2A1 as V gamma 9-binding protein mandatory for the PAg response but also insights gained from the identification of functional PAg-reactive V gamma 9V delta 2 T cells and BTN3 in the alpaca and phylogenetic comparisons. Finally, we discuss models of the molecular basis of PAg recognition and implications for the development of transgenic mouse models for PAg-reactive V gamma 9V delta 2 T cells.