IL-21-Mediated Potentiation of Antitumor Cytolytic and Proinflammatory Responses of Human Vγ9Vδ2 T Cells for Adoptive Immunotherapy

V gamma 9V delta 2 T lymphocytes are a major human gamma delta T cell subset that react against a wide array of tumor cells, through recognition of phosphorylated isoprenoid pathway metabolites called phosphoantigens. Immunotherapeutic protocols targeting V gamma 9V delta 2 T cells have yielded promising, yet limited, signs of antitumor efficacy. To improve these approaches, we analyzed the effects on gamma delta T cells of IL-21, a cytokine known to enhance proliferation and effector functions of CD8(+) T cells and NK cells. IL-21 induced limited division of phosphoantigen-stimulated V gamma 9V delta 2 T cells, but did not modulate their sustained expansion induced by exogenous IL-2. V gamma 9V delta 2 T cells expanded in the presence of IL-21 and IL-2 showed enhanced antitumor cytolytic responses, associated with increased expression of CD56 and several lytic molecules, and increased tumor-induced degranulation capacity. IL-21 plus IL-2-expanded V gamma 9V delta 2 T cells expressed higher levels of inhibitory receptors (e.g., ILT2 and NKG2A) and lower levels of the costimulatory molecule NKG2D. Importantly, these changes were rapidly and reversibly induced after short-term culture with IL-21. Finally, IL-21 irreversibly enhanced the proinflammatory Th1 polarization of expanded V gamma 9V delta 2T cells when added at the beginning of the culture. These data suggest a new role played by IL-21 in the cytotoxic and Th1 programming of precommitted Ag-stimulated gamma delta T cells. On a more applied standpoint, IL-21 could be combined to IL-2 to enhance gamma delta T cell-mediated antitumor responses, and thus represents a promising way to optimize immunotherapies targeting this cell subset. The Journal of Immunology, 2009, 182: 3423-3431.