Select Plant Tannins Induce IL-2R alpha Up-Regulation and Augment Cell Division in gamma delta T Cells

gamma delta T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding gamma delta T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the V delta 2 subset of human gamma delta T cells. V delta 1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel gamma delta T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of gamma delta T cells. We identified gamma delta T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat's Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human V delta 1 and V delta 2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced gamma delta T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of gamma delta T cells.