T-Cell Activation by Recombinant Receptors : CD 28 Costimulation Is Required for Interleukin 2 Secretion and Receptor-mediated T-Cell Proliferation but Does Not Affect Receptor-mediated Target Cell Lysis 1

Recombinant T-cell receptors with antibody-like specificity are successfully used to direct CTLs toward a MHC-independent immune response against target cells. Here we monitored the specific activation of receptor grafted CTLs in the context of CD28 costimulation. Peripheral blood T cells were retrovirally engrafted with recombinant anti-CD30 and anticarcinoembryonic antigen receptors, respectively, that harbor either the FceRI-g or the CD3-z intracellular signaling domain. Cross-linking of recombinant receptors by solid-phase bound ligand,i.e., CD30 and a carcinoembryonic antigen receptor-specific anti-idiotypic antibody, respectively, induces IFNg secretion that is further enhanced by CD28 costimulation of grafted T cells. Induction of interleukin (IL)-2 secretion, in contrast, requires CD28 costimulation in addition to receptor crosslinking, irrespective of T-cell preactivation by anti-CD3 monoclonal antibody plus IL-2 or by anti-CD3 monoclonal antibody plus anti-CD28 monoclonal antibody. Accordingly, induction of IL-2 secretion upon receptor cross-linking by membrane-bound antigen requires CD28/B7 costimulation whereas IFN-g secretion and cell proliferation does not. The efficiency of cytolysis by receptor-grafted CTLs does not depend on and is not affected by CD28 costimulation. The data demonstrate that CTL proliferation, cytokine secretion, and cytolysis upon receptor cross-linking are differentially modulated by CD28 costimulation and that cytolysis does not require B7 expression on target cells.