Gamma delta T cells from HIV+ donors can be expanded in vitro by zoledronate/interleukin-2 to become cytotoxic effectors for antibody-dependent cellular cytotoxicity

Abstract

Immunotherapy using γδ T cells capable of mediating antibody-dependent cellular cytotoxicity (ADCC) is a promising anti-human immunodeficiency virus (HIV) strategy. Approved aminobispohsphonate drugs, for example zoledronate (Zometa), stimulate γδ T cells in cancer patients, where they may promote direct tumor killing. Knowing that γδ T cells are modulated during HIV disease, documenting their responses and potential for controlling HIV is important. We investigated whether zoledronate/interleukin (IL)-2 could expand cytotoxic Vδ2 cells from HIV+ donors and whether these cells functioned in ADCC. Peripheral blood mononuclear cells from uninfected controls and HIV+ individuals receiving anti-retroviral therapy were treated with isopentenyl pyrophosphate (IPP) or zoledronate plus IL-2 to expand the Vδ2+ subset. Immunophenotyping and functional analyzes (cytotoxicity or cytokine expression) allowed us to compare cell properties from individual donors and to compare the responses to each stimulating agent. Zoledronate stimulated a greater expansion of Vδ2 cells in HIV+ individuals compared with phosphoantigen IPP, and these cells expressed CD16. CD56 expression (a marker for cytotoxic cells) was lower on zoledronate-expanded cells, consistent with significantly lower cytotoxicity against the Daudi tumor cell line. Cells expanded with either zoledronate or IPP were active in ADCC, were similar in terms of interferon (IFN)-γ and tumor necrosis factor (TNF)-α expression, and degranulated in response to Fc receptor cross-linking. Zoledronate causes ex vivo expansion of Vδ2 cells from HIV+ individuals. Despite lower expression of CD56 and decreased direct cytotoxicity, these effectors were potent in ADCC. Zoledronate/IL-2- expanded cells have potential for immunotherapy to activate Vδ2 cells in HIV patients and enhance ADCC.