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Signaling and CD28 Costimulation Are Simultaneously Required for Efficient IL-2 Secretion and Can Be Integrated Into One Combined CD28/CD3 Signaling Receptor Molecule1
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Klinik I für Innere Medizin, Labor Tumorgenetik, Universität zu Köln, Köln, Germany;
St. Elisabeth-Krankenhaus Köln-Hohenlind, Köln, Germany; and
Johannes Gutenberg-Universitat, III. Medizinische Klinik, Mainz, Germany
Recombinant immunoreceptors with specificity for the
carcinoembryonic Ag (CEA) can redirect grafted T cells to a
MHC/Ag-independent antitumor response. To analyze receptor-mediated
cellular activation in the context of CD28 costimulation, we generated:
1) CEA+ colorectal tumor cells that express simultaneously
B7-1 and B7-2, and 2) CEA-specific immunoreceptors that harbor
intracellularly the signaling moities either of CD28
(BW431/26-scFv-Fc-CD28), CD3
(BW431/26-scFv-Fc-CD3), or
Fc
RI
(BW431/26-scFv-Fc-). By retroviral gene transfer, we
grafted activated T cells from the peripheral blood with these
immunoreceptors. T cells that express the FcRI or CD3
signaling receptor lysed specifically CEA+ tumor cells and
secreted high amounts of IFN- upon receptor cross-linking, whereas
anti-CEA-CD28 receptor-grafted T cells did not, indicating that
CD28 signaling alone is not sufficient for efficient T cell activation.
CD28 costimulation did not affect cytolysis by T cells equipped with
- or -signaling receptors, but enhanced both IFN- secretion
and proliferation. CD28 costimulation, however, was required for
efficient IL-2 secretion of anti-CEA- receptor-grafted T cells.
Both purified CD4+ and CD8+ T cells grafted
with immunoreceptors required CD28 costimulation for complete T cell
activation. We integrated both CD28 and CD3 signaling domains into
one combined immunoreceptor molecule (BW431/26-scFv-Fc-CD28/CD3)
with dual signaling properties. T cells grafted with the combined
CD28/CD3 signaling receptor secreted high amounts of IL-2 upon Ag
binding without exogenous B7/CD28 costimulation, demonstrating that
both MHC-independent cellular activation and CD28 costimulation for
complete T cell activation can be delivered by one recombinant receptor
molecule.
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