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

Abstract

About 1–5% of human blood T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains contain a rearrangement of Vγ9 with JP (TRGV9JP or Vγ2Jγ1.2) and are paired with Vδ2 (TRDV2)-containing δ-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 Vγ9, Vδ2, and butyrophilin (BTN) 3 in various non-primate species identified candidate species possessing PAg-reactive Vγ9Vδ2 T cells. Here, we review the current knowledge of the molecular basis of PAg recognition. This not only includes human Vγ9Vδ2 T cells and the recent discovery of BTN2A1 as Vγ9-binding protein mandatory for the PAg response but also insights gained from the identification of functional PAg-reactive Vγ9Vδ2 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 Vγ9Vδ2 T cells.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“… 25 , 31 Importantly, recent insights revealed that the agonistic activity of mAb 20.1 also depended on cell surface-expressed BTN2A1. 35 The currently discussed model 38 of Vγδ2 T cell activation and the role of BTN molecules and pAgs are illustrated in Fig. 1 .…”

A glance over the fence: Using phylogeny and species comparison for a better understanding of antigen recognition by human γδ T‐cells

“…As an alternative, murine reporter cells can be used. 101,102,111,112 These cells do not express BTN3A1 but require overexpression by transduction of the costimulatory molecule CD28 on the reporter cell and of counter ligands such as CD80 on the presenting cells for efficient activation. 101,102,112 Already the first report on ing away from the membrane.…”

“…101,102,111,112 These cells do not express BTN3A1 but require overexpression by transduction of the costimulatory molecule CD28 on the reporter cell and of counter ligands such as CD80 on the presenting cells for efficient activation. 101,102,112 Already the first report on ing away from the membrane. 114 In contrast, introduction of a disulfide bridge between the C-domains, which fixes the V-conformation, diminished ABP-induced stimulation but did not affect ABP-induced mobility reduction in these BTN3A1 constructs, casting doubts on the significance of mobility changes in ABP-induced activation.…”

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“…These metabolites, such as the isopentenyl pyrophosphate (IPP), can accumulate in transformed and infected cells because of their dysregulated metabolism (127,135,137). IPP accumulates when the activity of the IPP-metabolizing enzyme farnesyldiphosphate-synthase (FPPS) is blocked (135). The use of aminobiphosphonates, such as zoledronate, inhibits FFPS, which leads to an increase in intracellular level of IPP and the activation of Vγ9Vδ2 T cells (135,(138)(139)(140).…”

“…IPP accumulates when the activity of the IPP-metabolizing enzyme farnesyldiphosphate-synthase (FPPS) is blocked (135). The use of aminobiphosphonates, such as zoledronate, inhibits FFPS, which leads to an increase in intracellular level of IPP and the activation of Vγ9Vδ2 T cells (135,(138)(139)(140).…”