Abstract
Most circulating human gamma delta T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains show a Vγ9-JP (Vγ2-Jγ1.2) rearrangement and are paired with Vδ2-containing δ-chains, a dominant TCR configuration, which until recently seemed to occur in primates only. Vγ9Vδ2 T cells respond to phosphoantigens (PAg) such as (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), which is produced by many pathogens and isopentenyl pyrophosphate (IPP), which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. A prerequisite for PAg-induced activation is the contact of Vγ9Vδ2 T cells with cells expressing butyrophilin-3 A1 (BTN3A1). We will first critically review models of how BTN3 might act in PAg-mediated Vγ9Vδ2 T cell activation and then address putative co-evolution of Vγ9, Vδ2, and BTN3 genes. In those rodent and lagomorphs used as animal models, all three genes are lost but a data-base analysis showed that they emerged together with placental mammals. A strong concomitant conservation of functional Vγ9, Vδ2, and BTN3 genes in other species suggests co-evolution of these three genes. A detailed analysis was performed for the new world camelid alpaca (Vicugna pacos). It provides an excellent candidate for a non-primate species with presumably functional Vγ9Vδ2 T cells since TCR rearrangements share features characteristic for PAg-reactive primate Vγ9Vδ2 TCR and proposed PAg-binding sites of BTN3A1 have been conserved. Finally, we analyze the possible functional relationship between the butyrophilin-family member Skint1 and the γδ TCR-V genes used by murine dendritic epithelial T cells (DETC). Among placental mammals, we identify five rodents, the cow, a bat, and the cape golden mole as the only species concomitantly possessing potentially functional homologs of murine Vγ3, Vδ4 genes, and Skint1 gene and suggest to search for DETC like cells in these species.
Highlights
Most circulating human gamma delta T cells are Vγ9Vδ2 T cells
Considering inherent qualities of T cell antigen receptors (TCR) clonotypes as the basis for their differential capacity in recognizing butyrophilin-3 A1 (BTN3A1)-ED-PAg complex or Butyrophilin 3 (BTN3)-monoclonal antibody (mAb) complex, we propose or speculate that some Vγ9Vδ2 TCR, e.g., TCR B2G9 preferentially bind to a complex of PAg bound to the BTN3A1-ED, whereas others would preferentially bind to the conformationally changed BTN3A1 whose ED does not need to be in complex with the PAg
Their paper opposes the interpretation of the BTN3-V domain crystallized in presence of PAg as BTN3-PAg complex [94]. Based on their analyses of the B30.2 domain and their own negative data on PAg- and TCR-binding, BTN3A1 is refuted as an “antigen-presenting molecule.”. They propose in the discussion section: “a model where PAg binding to the BTN3A1 intracellular domain (ID) results in recruitment of additional primate-specific factors and/or rearrangement of the BTN3A1 extracellular domain that generates a stimulatory signal directly detected by the Vγ9Vδ2 TCR
Summary
Most circulating human gamma delta T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains show a Vγ9-JP (Vγ2-Jγ1.2) rearrangement and are paired with Vδ2-containing δ-chains, a dominant TCR configuration, which until recently seemed to occur in primates only. Crystallographic analysis identified a positively charged pocket in this region (the presumed contacts with the PAg are marked in Figure 1B), which could accommodate a PAg. Isothermal calorimetry demonstrated PAg-binding to recombinant BTN3A1-ID, which was considerably stronger for HMBPP than for IPP and was extinguished by the same mutants, which abolished Vγ9Vδ2 TCR activation by respective BTN3 transductants.
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