A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling

Abstract

THE Fc receptor on B lymphocytes, FcγRIIB (β1 isoform), helps to modulate B-cell activation triggered by the surface immunoglobulin complex^1,2. Crosslinking of membrane immunoglobulin by antigen or anti-Ig F(ab′)₂ antibody induces a transient increase in cytosolic free Ca²⁺, a rise in inositol-3-phosphate, activation of protein kinase C, and enhanced protein tyrosine phosphorylation^3–5. Crosslinking FcγRIIB with the surface immunoglobulin complex confers a dominant signal that prevents or aborts lymphocyte activation triggered through the ARH-1 motifs of the signal transduction subunits Ig-α and Ig-β. Here we show that FcγRIIB modulates membrane immunoglobulin-induced Ca²⁺ mobilization by inhibiting Ca²⁺ influx, without changing the pattern of tyrosine phosphorylation. A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB is both necessary and sufficient for this effect. Tyrosine at residue 309 in this motif is phosphorylated upon co-crosslinking with surface immunoglobulin; mutation of this residue aborts the inhibitory effect of FcγRIIB. This inhibition is directly coupled to signalling mediated through Ig-α and Ig-β as evidenced by chimaeric IgM/α and IgM/β molecules. The 13-residue motif in FcyRIIB controls lymphocyte activation by inhibiting a Ca²⁺ sig-nalling pathway triggered through ARH-1 motifs as a result of recruitment of novel SH2-containing proteins that interact with this FcγRIIB cytoplasmic motif.