FcRs, the third type of immunoreceptors Activating FcRs Inhibitory FcRs Activating and inhibitory FcRs in physiology and pathology

Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders. Correspondence: Dr. Marc Daëron, Unité d’Allergologie Moléculaire et Cellulaire, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France. E-mail: [email protected] Tel. : +33-1-4568-8642, Fax : +33-1-4061-3160. H l-P ateur athor m anscript paste0269372, version 1 Hal-Pasteur author manuscript Advances in Immunology 89 (2006) 39-86 H l-P ateur athor m anscript paste0269372, version 1