Cutting edge: Human FcRL4 and FcRL5 are receptors for IgA and IgG

Fc receptor-like (FcRL) proteins are a family of cellular receptors homologous to FcγRI and are predominantly expressed by B cells. They function to costimulate or inhibit BCR signaling through consensus ITAMs and ITIMs; however, the extracellular ligands of these receptors remain unknown or controversial. In this study, we tested the ability of human FcRL proteins to bind Igs and found FcRL4 and FcRL5 to be bona fide Fc receptors. In cellular binding assays, FcRL4 bound efficiently to IgA and FcRL5 binds all IgG isotypes with varied efficiency. Additionally, we generated mAbs capable of specifically blocking these interactions. Given their expression on activated B cells and potential for inhibitory signaling, FcRL4 and FcRL5 are likely to be important for immune complex-dependent human B cell regulation, and they represent novel therapeutic targets for receptor blockade therapies.