Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-Like Immunoreceptor This information is current as of September 26, 2021. Andreas Hombach, Heike Köhler, Gunter Rappl and Hinrich Abken J Immunol 2006; 177:5668-5675; ; doi: 10.4049/jimmunol.177.8.5668 http://www.jimmunol.org/content/177/8/5668 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology

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

Andreas Hombach, Heike Ko¨hler, Gunter Rappl, and Hinrich Abken2

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 redi recting 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 Downloaded from 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؉ 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 Journal of Immunology, 2006 177: 5668–5675. http://www.jimmunol.org/ major hurdle in the immunotherapy of malignant dis- molecule, e.g., the Fc␧RI receptor ␥-chain or the CD3 ␨-chain, eases by adoptively transferred CD8ϩ CTL is their de- capable to drive T cell activation. T cells equipped with such type A pendency on CD4ϩ Th cells, which require Ag-specific of immunoreceptors induce an Ag-specific cellular immune re- activation to provide help in the eradiation of tumor cells (1, 2). By sponse in vitro and in vivo, indicated by induction of cytokine release of cytokines and interaction with professional APCs, secretion, T cell proliferation, and target cell lysis (6–8). By cir- CD4ϩ T cells recruit innate immune and nonimmune effector cells cumventing their restriction to MHC-I and MHC-II, respectively, to exhibit their antitumor activity (3, 4). However, the majority of both CD8ϩ and CD4ϩ T cells can be activated upon triggering tumor cells lack MHC class II (MHC-II)3 expression, thereby pre- with an Ab-type im