ANTIGEN-SPECIFIC CYTOLYSIS BY NEUTROPHILS AND NK CELLS EXPRESSING CHIMERIC IMMUNE RECEPTORS BEARING ZETA OR GAMMA SIGNALING DOMAINS

TCR-and IgG-binding Fe receptors (Fc gamma R) mediate a variety of cri tical biologic activities including cytolysis via the structurally rel ated zeta- and gamma-chains, In previous studies, we have described ch imeric immune receptors (CIR) in which the ligand-binding domain of a heterologous receptor or Ab is fused directly to the cytoplasmic domai n of the TCR zeta-chain. Such zeta-CIRs efficiently trigger cytotoxic function of both T and NK cells in a target-specific manner. In this r eport, we compared the ability of both zeta- and zeta-CIRs to activate the cytolytic function of two distinct classes of Fc zeta R-bearing e ffecters, NK cells and neutrophils. Mature neutrophils expressing zeta - and gamma-CIR were generated in vivo from murine hemopoietic stem ce lls following transplantation of syngeneic mice with retrovirally tran sduced bone marrow or in vitro from transduced human CD34(+) progenito rs following differentiation. Both zeta- and gamma-based CIRs were cap able of activating target-specific cytolysis by both NK cells and neut rophils, although the zeta-CIR was consistently more efficient. The ex perimental approach described is a powerful one with which to study th e role of nonlymphoid effector cells in the host immune system and per mits the rational design of immunotherapeutic strategies that rely on harnessing multiple immune cell functions via CIR-modified hemopoietic stem cells or progenitors.