Conservation of Nonpeptide Antigen Recognition by Rhesus Monkey Vγ2Vδ2 T Cells

Abstract

We have previously found that monkey Vγ2Vδ2+ T cells mount adaptive immune responses in response to Mycobacterium bovis bacillus Calmette-Guérin infections. We have now analyzed rhesus monkey γδ T cell responses to nonpeptide Ags and superantigens. Like human Vγ2Vδ2+ T cells, rhesus monkey γδ T cells are stimulated when exposed to prenyl pyrophosphate, bisphosphonate, and alkylamine Ags. Responsiveness was limited to γδ T cells expressing Vγ2Vδ2 TCRs. Rhesus monkey Vγ2Vδ2+ T cells also responded to the superantigen, staphyloccocal enterotoxin A. Sequencing of the rhesus monkey Vγ2Vδ2 TCR revealed a strong sequence homology to human Vγ2Vδ2 TCR that preserves important sequence motifs. Moreover, chimeric TCRs that pair human Vγ2 with monkey Vδ2 and monkey Vγ2 with human Vδ2 retain reactivity to nonpeptide Ags and B cell lymphomas. A molecular model of the rhesus monkey Vγ2Vδ2 TCR has a basic region in the complementarity-determining region 3 binding groove that is similar to that seen in the human Vγ2Vδ2 TCR and preserves the topology of the complementarity-determining region loops. Thus, recognition of nonpeptide prenyl pyrophosphate, bisphosphonate, and alkylamine Ags is conserved in primates suggesting that primates can provide an animal model for human γδ T cell Ag responses.

Innate-like γδ T cell responses to mycobacterium Bacille Calmette-Guerin using the public Vγ2 repertoire in Macaca fascicularis

“…In healthy human adults, the Vγ2-Jγ1.2 rearrangement accounts for more than 70% of Vγ2 chains in peripheral blood 20,23 . Similar results were obtained for Macaca mulatta 24,25 and Macaca fascicularis 26 monkeys although we know that monkeys have some cells expressing Vγ2 chains paired with Vδ1 27 (a combination that is infrequent for adult human beings) and that subset will influence the repertoire. The Vγ2-Jγ1.2+ subset responds to a variety of pathogens [28][29][30][31][32][33] and tumor cells [34][35][36][37][38][39][40] .…”

Select Plant Tannins Induce IL-2Rα Up-Regulation and Augment Cell Division in γδ T Cells

“…The best-defined agonists that drive ␥␦ T cell expansion are phosphoantigens, but they are specific to human and non-human primate cells (19) making in vivo studies difficult. Limited studies in non-human primates demonstrate proof-of-principle that ␥␦ T cells expand in vivo (20), but efficacy studies have not been reported in these animals.…”

“…Notably, phosphoantigen-based proliferation requires a costimulatory factor for optimal V␦2 T cell expansion, typically IL-2 or IL-15 (16 -18). Though expansion of V␦2 T cells in vivo is clearly demonstrated using these new drugs, the benefit of these expanded cells on host defenses is not fully understood due to a minimal or nonexistent response in non-primate animal models (19). Additional caveats for the clinical use of phosphoantigen-based drugs include the requirement for large amounts of agonist (20), induction of rapid cell anergy to treatment (20), and activation of only the V␦2 subset, which must then traffic to the tumor or infection to be effective (8,12,20,21).…”

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

“…64 These special canonical Vc9Vd2 T cells recognize non-peptidic phosphorylated antigens, such as isopentyl pyrophosphate (IPP), that are metabolites in the essential isoprenoid biosynthesis pathway present in virtually all living organisms. 6 Endogenously, IPP and its stereoisomer dimethylallyl diphosphate are substrates produced in the mevalonate pathway for cholesterol metabolism; however, they can also be produced by the deoxyxylulose pathway commonly used by organisms, such as Escherichia coli and certain plant cells, that lack the critical HMGCoA reductase enzyme of the mevalonate pathway.…”