Human CD4+ T cells lyse target cells via granzyme/perforin upon circumvention of MHC class II restriction by an antibody-like immunoreceptor.
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-alpha 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-alpha. 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.
Hombach
Andreas
A
Klinik I für Innere Medizin, Labor Tumorgenetik, and Zentrum für Molekulare Medizin Köln, Universität zu Köln, Köln, Germany.
Köhler
Heike
H
Rappl
Gunter
G
Abken
Hinrich
H
D000912:Antibodies, Neoplasm / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D053804:Granzymes; D000949:Histocompatibility Antigens Class II; D006801:Humans; D008562:Membrane Glycoproteins; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015202:Protein Engineering / Q000379:methods; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins; D037182:T-Cell Antigen Receptor Specificity; D014407:Tumor Cells, Cultured
D000912:Antibodies, Neoplasm; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D054353:Perforin; D053804:Granzymes