title: Trans-inhibition of activation and proliferation signals by Fc receptors in mast cells and basophils.
abstract: Allergic and autoimmune inflammation are associated with the activation of mast cells and basophils by antibodies against allergens or auto-antigens, respectively. Both cell types express several receptors for the Fc portion of antibodies, the engagement of which by antigen-antibody complexes controls their responses. When aggregated on the plasma membrane, high-affinity immunoglobulin E (IgE) receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA in mice, FcγRIIA in humans) induce these cells to release and secrete proinflammatory mediators, chemokines, and cytokines that account for clinical symptoms. When coaggregated with activating receptors on the same cells, other low-affinity IgG receptors (FcγRIIB in both species) inhibit mast cell and basophil activation. We found that FcγRIIB inhibited not only signals triggered by activating receptors with which they were coengaged (cis-inhibition), but also signals triggered by receptors engaged independently (trans-inhibition). Trans-inhibition acted upon the FcεRI-dependent activation of mouse mast cells, mouse basophils, and human basophils, and upon growth factor receptor (Kit)-dependent normal mouse mast cell proliferation, as well as the constitutive in vitro proliferation and the in vivo growth of oncogene (v-Abl)-transformed mastocytoma cells. Trans-inhibition was induced by receptors, whether inhibitory (FcγRIIB) or activating (FcεRI), which recruited the lipid phosphatase SHIP1. By hydrolyzing PI(3,4,5)P3, SHIP1 induced a global unresponsiveness that affected biological responses triggered by receptors that use phosphoinositide 3-kinase to signal. These data suggest that trans-inhibition controls numerous physiological and pathological processes, and that it may be used as a therapeutic tool in inflammation, especially but not exclusively, in allergy and autoimmunity.
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.|Inserm, Unité 760, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Malbec
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.|Inserm, Unité 760, Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Cassard
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.|Inserm, Unité 760, Paris, France.
authors.forename: Marcello
authors.initials: M
authors.lastname: Albanesi
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.|Inserm, Unité 760, Paris, France.
authors.forename: Friederike
authors.initials: F
authors.lastname: Jönsson
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.|Inserm, Unité 760, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Mancardi
authors.affiliation: Inserm, Unité 1048, Toulouse, France.|Université Toulouse 3, Toulouse, France.|Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.affiliation: Inserm, Unité 1048, Toulouse, France.|Université Toulouse 3, Toulouse, France.|Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.affiliation: Inserm, Unité 1068, Centre de Recherche en Cancérologie de Marseille, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|Aix Marseille Université, Marseille, France.|CNRS, UMR 7258, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.|Hôpital de la Conception, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France. marc.daeron@pasteur.fr.|Inserm, Unité 760, Paris, France.|Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Daëron
mesh_terms: D000818:Animals; D001491:Basophils / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D008407:Mast Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C517507:FcgammaRIIIA protein, mouse; C499172:Fcgr2b protein, mouse; D018129:Phosphatidylinositol Phosphates; D017455:Receptors, IgE; D017452:Receptors, IgG; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases