title: Persistent CD3-crosslinking down-regulates interleukin-2 responsiveness in interleukin-2-competent cloned T cells: the possible involvement of protein kinase C.
abstract: To investigate the regulation of interleukin-2 (IL-2) responsiveness of T cells, a human CD4+ T-cell clone with constitutive expression of IL-2 receptors was stimulated with recombinant IL-2 (rIL-2) in the presence or absence of immobilized anti-CD3 monoclonal antibodies (alpha CD3imm MoAb). Incubation of T cells with alpha CD3imm MoAb decreased IL-2-induced proliferation which could not be ascribed to the modulation of IL-2 receptor expression nor to cell death. Phorbol-myristate-acetate (PMA), an activator of protein kinase C (PKC), also induced down-regulation of IL-2 responsiveness. The alpha CD3sol MoAb, inducing Ca(2+)-mobilization without activating PKC, did not inhibit IL-2 responsiveness whereas cyclosporine A (CsA), a drug that inhibits the Ca(2+)-dependent activation pathway, did not prevent the induction of IL-2 hyporesponsiveness induced by alpha CD3imm MoAb. It is concluded that modulation of IL-2 responsiveness of T cells via the T-cell receptor/CD3 complex (TCR/CD3) may be mediated by a PKC-activating signal.
authors.affiliation: Department of Rheumatology, Leiden University Hospital, The Netherlands.
authors.forename: R B
authors.initials: RB
authors.lastname: Landewé
authors.forename: B A
authors.initials: BA
authors.lastname: Dijkmans
authors.forename: M J
authors.initials: MJ
authors.lastname: Verdonk
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: M R
authors.initials: MR
authors.lastname: Daha
authors.forename: A M
authors.initials: AM
authors.lastname: Miltenburg
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001667:Binding, Competitive / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism*; D002999:Clone Cells; D003432:Cross-Linking Reagents; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D007376:Interleukin-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D011493:Protein Kinase C