title: Isotype-specific cross-linking of select human Fc gamma R isoforms triggers release of IL-6.
abstract: Anti-CD3 MoAbs are widely used in T cell activation studies, and are effective in immunosuppressive therapy. We used a panel of mouse (m) anti-CD3 switch variant MoAbs of five different isotypes to study IL-6 release from accessory cells. Incubation of human (h) mononuclear cells with anti-CD3 MoAbs resulted in increased IL-6 levels with MoAbs of mIgG1 and mIgG2a isotypes, with no effect of mIgG2b or mIgA. This suggested involvement of IgG Fc receptors (Fc gamma R) in triggering IL-6 production. To evaluate the role of different Fc gamma R molecules individually we used a panel of hFc gamma R-transfected mouse fibroblasts, and Jurkat T cells as a model. IL-6 secretion by CD32 transfectants expressing the hFc gamma RIIa high-responder (HR) allelic form was triggered by mIgG1 anti-CD3 MoAb, with no effect of four other isotypes. None of the anti-CD3 MoAbs induced IL-6 secretion by CD32 transfectants expressing either a variant of this receptor, containing only a single intracellular amino acid (CT-), the hFc gamma RIIa low-responder (LR) allelic form, or hFc gamma RIIb1. hFc gamma RI (CD64) transfectants exhibited IL-6 production after incubation with mIgG2a anti-CD3 MoAb, and to a lesser extent with mIgG2b, and mIgG1 MoAb. Indirect involvement of T cells in triggering IL-6 secretion could be excluded by experiments in which transfectants were cultured with immobilized anti-CD3 MoAb. These data indicate that cross-linking of either hFc gamma RI, or hFc gamma RIIaHR by appropriate anti-CD3 MoAbs triggers IL-6 production of accessory cells, and not T cells. This may also take place in vivo during immunosuppressive therapy with anti-CD3 MoAbs, and related antibody-mediated immune responses.
authors: Department of Immunology, University Hospital Utrecht, The Netherlands.
authors: A J
authors: AJ
authors: Duits
authors: L A
authors: LA
authors: Aarden
authors: L K
authors: LK
authors: Ernst
authors: P J
authors: PJ
authors: Capel
authors: J G
authors: JG
authors: van de Winkel
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D011940:Receptor Aggregation; D017452:Receptors, IgG / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007132:Immunoglobulin Isotypes; D015850:Interleukin-6; D017452:Receptors, IgG