The Vγ9Vδ2T cell antigen receptor and butyrophilin-3 A1: models of interaction, the possibility of co-evolution, and the case of dendritic epidermalT cells

Most circulating human gamma delta T cells are V gamma 9V delta 2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose gamma-chains show a V gamma 9-JP (V gamma 2-J gamma 1.2) rearrangement and are paired with V delta 2-containing delta-chains, a dominant TCR configuration, which until recently seemed to occur in primates only. V gamma 9V delta 2 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 V gamma 9V delta 2 T cells with cells expressing butyrophilin-3 A1 (BTN3A1). We will first critically review models of how BTN3 might act in PAg-mediated V gamma 9V delta 2 T cell activation and then address putative co-evolution of V gamma 9, V delta 2, 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 V gamma 9, V delta 2, 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 V gamma 9V delta 2 T cells since TCR rearrangements share features characteristic for PAg-reactive primate V gamma 9V delta 2 TCR and proposed PAg-binding sites of BTN3A1 have been conserved. Finally, we analyze the possible functional relationship between the butyrophilin-family member Skintl and the gamma delta 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 V gamma 3, V delta 4 genes, and Skint1 gene and suggest to search for DETC like cells in these species.