CD28 costimulation overcomes transforming growth factor-beta-mediated repression of proliferation of redirected human CD4+ and CD8+ T cells in an antitumor cell attack.
The T-cell-mediated antitumor immune response is frequently repressed in the tumor environment by an immunologic barrier, the predominant mediators of which are thought to be interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). We explored the effect of these cytokines on the individual T-cell effector functions on antigen engagement during an antitumor cell attack. Isolated CD4+ and CD8+ T cells were antigen-specifically redirected toward carcinoembryonic antigen (CEA)-positive tumor cells by expression of a recombinant T-cell receptor (immunoreceptor), which triggers T-cell activation via CD3zeta on binding to CEA. Immunoreceptor-activated T cells secrete IFN-gamma, proliferate, and lyse CEA+ but not CEA- tumor cells. Whereas IL-10 has no direct effect on immunoreceptor-triggered effector functions, TGF-beta represses proliferation of both CD4+ and CD8+ T cells but neither IFN-gamma secretion nor specific cytolytic activities. CD28 costimulation, however, overcomes TGF-beta-mediated repression in T-cell proliferation. Consequently, T cells redirected by a combined CD28-CD3zeta signaling immunoreceptor are largely resistant to TGF-beta-mediated repression. This is reflected in vivo by a more pronounced antitumor activity of T cells against TGF-beta-secreting tumors when redirected by a costimulatory CD28-CD3zeta than by a CD3zeta signaling immunoreceptor.
Koehler
Heike
H
Tumorgenetik, Klinik I für Innere Medizin and Zentrum für Molekulare Medizin Köln, Universität zu Köln, Kerpener Strasse 62, D-50924 Köln, Germany.
Kofler
David
D
Hombach
Andreas
A
Abken
Hinrich
H
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D006801:Humans; D007111:Immunity, Cellular; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016212:Transforming Growth Factor beta