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Immunotherapeutic approaches involving genetic modification of T cells show promise in generating highly specific tumor-reactive effector cells for cancer treatment. Given the high affinity of Fc e RI (the subtype I Fc receptor for IgE) for IgE monoclonal antibody (mAb), modification of T cells with chimeric Fc e RI in combination with tumor-specific IgE mAbs is potentially a powerful and effective strategy to specifically target T cells to tumor cells. In this study, we retrovirally transduce human primary T cells with a cDNA encoding the extracellular domain of Fc e RI linked to the hinge and transmembrane domains of Fc γ RI and the cytoplasmic domains of CD28 and T cell receptor ζ chain (Fc e RI-CD28-ζ). We demonstrate that human T cells expressing Fc e RI-CD28-ζ, in the presence of tumor-specific IgE mAb recognizing mouse CD8 antigen (Ly- 2.1+), can specifically secrete cytokine, proliferate, and mediate cytotoxic function after antigen ligation. Furthermore, adoptive transfer of Fc e RI-CD28-ζ cells ...