αβ T-cell receptor engineered γδ T cells mediate effective antileukemic reactivity

Retroviral transfer of T-cell receptors (TCR) to peripheral blood-derived T cells generates large numbers of T cells with the same antigen specificity, potentially useful for adoptive immunotherapy. One drawback of this procedure is the formation of mixed TCR dimers with unknown specificities due to pairing of endogenous and introduced TCR chains. We investigated whether gamma delta T cells can be an alternative effector population for TCR gene transfer because the gamma delta TCR is not able to form dimers with the alpha beta TCR. Peripheral blood-derived gamma delta T cells were transduced with human leukocyte antigen (HLA) class I- or HLA class II-restricted minor histocompatibility antigen (mHag) or virus-specific TCRs. Because most gamma delta T cells do not express CD4 and CD8, we subsequently transferred these coreceptors. The TCR-transduced gamma delta T cells exerted high levels of antigen-specific cytotoxicity and produced IFN-gamma and IL-4, particularly in the presence of the relevant coreceptor. gamma delta T cells transferred with a TCR specific for the hematopoiesis-specific mHag HA-2 in combination with CD8 displayed high antileukemic reactivity against HA-2-expressing leukemic cells. These data show that transfer of alpha beta TCRs to gamma delta T cells generated potent effector cells for immunotherapy of leukemia, without the expression of potentially hazardous mixed TCR dimers.