Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells.
In current clinical trials, chimeric antibody-like receptors fused to signaling domains derived from TCR-zeta or Fc(epsilon)RIgamma-chain are tested for their ability to lyse tumor cells in vivo. In this study, the function of primary T cells expressing such receptors has been investigated in transgenic mice. These receptors cannot induce proliferation of resting T cells or trigger the production of optimal amounts of cytokines. It is further demonstrated that an initial low presence of cytokine message and protein is disappearing rather fast, whereas the triggering of endogenous TCR/CD3 in the same cells leads to normal prolonged cytokine production. The direct clinical relevance of these findings is further underlined by the increased in vivo tumor rejection by T cells expressing chimeric receptors in presence of exogenous interleukin-2. Therefore, adoptive T-cell therapy using primary T cells transfected with single chain receptors might benefit substantially from the accompanying administration of cytokines. (Blood. 2000;96:1999-2001)
Brocker
T
T
Institute for Biology III, Department of Molecular Immunology at the Max-Planck-Institute for Immunobiology, Basel, Switzerland. tbrocker@gmx.de
D000818:Animals; D017252:CD3 Complex / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics; D007376:Interleukin-2 / Q000008:administration & dosage; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D016207:Cytokines; D007128:Immunoglobulin Fragments; D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C061836:antigen T cell receptor, epsilon chain; C054979:antigen T cell receptor, zeta chain; C055966:immunoglobulin Fv