Human γδ-T Cells in Adoptive Immunotherapy of Malignant and Infectious Diseases

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Abstract
Human gammadelta-T cells are capable of mediating both innate antitumor and antiviral activity, functions that theoretically might be exploitable in the treatment of a variety of malignant or infectious diseases. Nonetheless, experimental therapies incorporating the adoptive transter of human gammadelta-T cells have remained unfeasible to date owing largely to the difficulty of isolating or expanding sufficient numbers of gammadelta-T cells. It is in this context that recent discoveries from our laboratory are presented. By identifying specific signaling pathways that selectively inhibit activation-induced apoptosis in apoptosis-prone gammadelta-T cells, we have been able to expand large numbers of viable and functional human gammadelta-T cells, an undertaking until now notpossible. As important, these apoptosis-resistant gammadelta-Tcells appear to retain major histocompatibility complex-unrestricted (innate) antitumor activity against a wide variety of human tumor cells both in vitro and in vivo. Moreover, apoptosis-resistant gammadelta-T cells also display potent innate antiviral activity in vitro against human immunodeficiency virus-1. Both the biologic and practical implications of these findings are considered and discussed particularly as they relate to the development of future adoptive immunotherapy strategies.