The Fc gamma receptor IIB (Fc γ RIIB/CD32B) was generated million years ago during evolution. It is the sole inhibitory receptor for IgG, and has long been associated with the regulation of humoral immunity and innate immune homeostasis. However, new and surprising functions of Fc γ RIIB are emerging. In particular, Fc γ RIIB has been shown to perform unexpected activatory roles in both immune-signaling and monoclonal antibody (mAb) immunotherapy. Furthermore, although ITIM signaling is an integral part of Fc γ RIIB regulatory activity, it is now clear that inhibition/activation of immune responses can occur independently of the ITIM. In light of these new findings, we present an overview of the established and noncanonical functions of Fc γ RIIB and discuss how this knowledge might be exploited therapeutically.
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