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Human CD4⁺ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-Like Immunoreceptor¹

Klinik I für Innere Medizin, Labor Tumorgenetik, and Zentrum für Molekulare Medizin Köln, Universität zu Köln, Köln, Germany

Immune elimination of tumor cells requires the close cooperation between CD8⁺ CTL and CD4⁺ Th cells. We circumvent MHC class II-restriction of CD4⁺ T cells by expression of a recombinant immunoreceptor with an Ab-derived binding domain redirecting specificity. Human CD4⁺ T cells grafted with an immunoreceptor specific for carcinoembryonic Ag (CEA) are activated to proliferate and secrete cytokines upon binding to CEA⁺ target cells. Notably, redirected CD4⁺ T cells mediate cytolysis of CEA⁺ tumor cells with high efficiencies. Lysis by redirected CD4⁺ T cells is independent of death receptor signaling via TNF- or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-. CD4⁺ T cells redirected by Ab-derived immunoreceptors in a MHC class II-independent fashion substantially extend the power of an adoptive, Ag-triggered immunotherapy not only by CD4⁺ T cell help, but also by cytolytic effector functions. Because cytolysis is predominantly mediated via granzyme/perforin, target cells that are resistant to death receptor signaling become sensitive to a cytolytic attack by engineered CD4⁺ T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe), Bonn, Deutsche Forschungsgemeinschaft, Bonn, Fortune program of the Medical Faculty of the University of Cologne.

² Address correspondence and reprint requests to Dr. Hinrich Abken, Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Josef Stelzmann Strasse 9, D-50924 Köln, Germany. E-mail address: hinrich.abken{at}uk-koeln.de

³ Abbreviations used in this paper: MHC-II, MHC class II; scFv, single-chain Ab fragment; Fas-L, Fas ligand; CEA, carcinoembryonic Ag; XTT, 2,3-bis(2-methoxy-4-nitro-5-sulphonyl)-5((phenyl-amino)carbonyl)-2H-tetrazolium hydroxide.

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