Abstract
An extended family of Fc receptor-like (FCRL) molecules has tyrosine-based signaling properties and is preferentially expressed by B lineage cells. In mice, FCRL5 is distinguished by its discrete expression among innate B lineage lymphocytes including splenic marginal zone B cells and peritoneal cavity-derived B1 B cells. FCRL5 has five Ig-like extracellular domains and a cytoplasmic tail containing an ITAM-like sequence and a consensus ITIM. To evaluate its signaling functionality, chimeric receptors comprised of the extracellular and transmembrane portions of FcγRIIb in frame with cytoplasmic Y>F variants of FCRL5 were generated in the mouse A20-IIA1.6 B cell line. Pervanadate treatment of chimeric transductants revealed that both tyrosine-based motifs can be phosphorylated. Coligation of the unmodified FcγRIIb/FCRL5 chimeric receptor with the B cell receptor (BCR) inhibited calcium mobilization, whole cell tyrosine phosphorylation, and Erk kinase activation via the ITIM-dependent (Y566) recruitment of the SHP-1 phosphatase. Conversely, coligation of a chimeric mutant bearing the intact ITAM-like (Y543/Y556) sequence with the BCR resulted in subtle but consistent enhancement of calcium mobilization. This activation effect correlated with the recruitment of the Src-family kinase, Lyn. The inhibitory influence of FCRL5 was similarly observed in primary splenic marginal zone B cells. These data indicate that FCRL5 serves as a dominant inhibitory co-receptor in B cells.
