~ 13 amino acid sequence (AENTITYSLLKHP) has been identified in the intracytoplasmic domain of murine Fc~,RIIBI as being necessary for this receptor to inhibit B-cell activationL Fc3,RIIBI is an isoform of the low-affinity receptors for lgG encoded by the Fc~/RIIB gene, and is expressed on murine B cells 2. It mediates the immunoregulatory properties of lgG immune complexes (reviewed in ReL 3) and IgG anti-immuooglobulin antibodiesL lgG antibodies inhibit B-cell activation by coaggregating Fc~,RIIB1 and the B-cell receptor for antigen (BCR). Human Fc',/RIIB-mediated negative regulation has been demonstrated both in murine v and human" B cells, and the same highly conserved sequence was found to be necessary ~ and sufficient: for inhibiting B-cell activation in the two species.
Alti~ough typically regarded as a B-cell-specific mechanism, Fc'yRllB-mediated negative regulation was extended to other re-cepto~ whose cell-triggering ability depends on immunoreceptor tyrosine-based activation motifs (ITAMs). Fc'vRIIB receptors are widely expressed by cells of the lymphoid and myeloid lineages, and mouse F~RIIB was shown to inhibit Fc~Rl-dependent mastcell activation s, and T-cell receptor (TCRl-dependent T-cell activation". Similarly, human Fc',/RIIB can inhibit Fc~Rl-and Fe~,RllAdependent mast-cell activation ~. The same 13 amino acid ~equence was required for inhibition of cell activation, irrespective of the ITAM-bearing cell-activating receptor". Fc~/RIIB was also found to inhibit cells activated by single-chain chimeric molecules bearing the intracytoplasmic domain of lg-t~ (Ref. 7), FeRn/or CD3~ (Ref. 9) polypeptides, suggesting that all receptors associat~.~ with these subunits are regulated by Fc3,RIIB. This was confirmed for mT~rine FevRIIIA in Fc~,RllB-deficient mice"'. Thus, rather than a B-cellspecific regulatory, molecule, Fc"/RIIB is a general, negative coreceptor for all ITAM-bearing receptors expressed by hematopoietic cells.
Structural and functional characteristics of the
Fc~/RIIB inhibitory motif
A tyrosme and a leucine residue, separatL~ by two amino acids (YSLL), in the 13 amino acid sequence were found to be mandatory. for Fc"/RlIB-dependent inhibition. Following coaggregation with ITAM-bearing receptors, the tyrosine residue is phosphorylated 7, and Fc~/RIIB becomes a potential ligand for src-homology 2 (SH2)-JUNE 1997 Cells that are activated following ligation of recel,tors bearing immunoreceptor tyrosine-based activation motifs (ITAMs) can be negatively rey, ulated by other receptar,~ bearing i.t.llHlorcceptt,r