Vgamma9Vdelta2 T cells: Identification in non-primate species and dissection of molecular determinants of antigen-recognition

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Vgamma9Vdelta2 T cells are effectors of human immune responses against pathogens and tumors. Their T cell antigen receptors (TCR) recognize small pyrophosphorylated metabolites (phosphoantigens: PAg) of host or microbial-isoprenoid-synthesis in conjunction with the cell surface molecule BTN3A1. So far these cells have been found only in primates. Very recently. we found genes for Vgamma9Vdelta2 TCR and its ligand BTN3A1 in several rather distantly related placental mammals, among them alpaca (Vicugna pacos), where functional expression of these genes was directly demonstrated. The major aim of the project is to directly identify and functionally characterize Vgamma9Vdelta2 T cells in alpaca as first non-primate species. At first, monoclonal antibodies against Vgamma9Vdelta2 TCR and BTN3A1 shall be generated. These antibodies will be used to directly identify alpaca Vgamma9Vdelta2 T cells in peripheral blood of alpaca and to investigate whether they can be activated in a PAg and BTN3A1 dependent fashion. If yes, alpaca may represent a model to study Vgamma9Vdelta2 T cells in naturally occurring infections. If alpaca Vgamma9Vdelta2 T cells lack PAg reactivity, the molecular basis of this functional difference will be addressed by trying to reconstitute a response towards PAg: Either by expressing candidate molecules from primates in alpaca cells or constructs of the alpaca BTN3A1 in primate cells. The opportunity to work with camelid gamma-delta T cells shall also be used to track recently published somatic hypermutations of gamma-delta TCRs in alpaca and other camelids. Finally, we are aiming to identify Vgamma9Vdelta2T cells in further mammalian species. The prime candidate would be the nine-banded armadillo (Dasypus novemcinctus) which is of special interest i) as natural host of Mycobacterium leprae and ii) as a member of the superorder xenarthra, which is assigned to a different clade of placental mammals than alpaca and humans. Altogether, we expect from analysis of these rather distantly related species new insights in the general physiology of gamma-delta T cells.