The Vγ9Vδ2 T Cell Antigen Receptor and Butyrophilin-3 A1: Models of Interaction, the Possibility of Co-Evolution, and the Case of Dendritic Epidermal T Cells

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.

Osteonecrosis of the Jaw Developed in Mice

“…It has been established that the V␥9V␦2 T cell receptor as well as butyrophilin-3A1 critical for IPP-induced activation of ␥␦ T cells are conserved only in humans, primates, and a few other placental animals but not in mice (39,40). Therefore, mouse ␥␦ T cells do not respond to pAgs, and the ZOL injection should not activated the circulating ␥␦ T cells in mice through a similar mechanism as in humans.…”

Evolution and function of the TCR Vgamma9 chain repertoire: It’s good to be public

“…BTN3A1 most likely interacts with additional molecules in accessory cells in order to elicit Vgamma9Vdelta2 T cell responses [94, 95] but it alone is insufficient for phosphoantigen responses and must be supplemented by other, yet unidentified molecules encoded on human chromosome 6 [94]. The role of BTN3A1 has been discussed extensively in recent reviews [96, 97] including a contribution from Erin Adams in this issue. The evolving story of BTN3A1 drives home the uncomfortable but interesting idea that stimulation and effector function of Vgamma9Vdelta2 T cells may require a ligand, which has not been identified.…”

Regulation of Immunity by Butyrophilins

“…The directinteraction model, reviewed extensively in the literature (79)(80)(81)(82), mimics other mechanisms of bacterial metabolite presentation to specialized cells of the immune system. MR1-dependent presentation of vitamin B derivatives to MAIT cells (83,84) (see sidebar MR1-Restricted Presentation of Bacterial Metabolites to MAIT Cells; 85) and CD1d-restricted presentation of lipid to the invariant TCR on natural killer T (NKT) cells (86) both rely upon MHC class I-like structures for antigen presentation to their respective TCRs.…”