Antigen-Induced Oligomerization of the B Cell Receptor Is an Early Target of FcγRIIB Inhibition

The Fc gamma RIIB is a potent inhibitory coreceptor that blocks BCR signaling in response to immune complexes and, as such, plays a decisive role in regulating Ab responses. The recent application of high-resolution live cell imaging to B cell studies is providing new molecular details of the earliest events in the initiation BCR signaling that follow within seconds of Ag binding. In this study, we report that when colligated to the BCR through immune complexes, the Fc gamma RIIB colocalizes with the BCR in microscopic clusters and blocks the earliest events that initiate BCR signaling, including the oligomerization of the BCR within these clusters, the active recruitment of BCRs to these clusters, and the resulting spreading and contraction response. Fluorescence resonance energy transfer analyses indicate that blocking these early events may not require molecular proximity of the cytoplasmic domains of the BCR and Fc gamma RIIB, but relies on the rapid and sustained association of Fc gamma RIIB with raft lipids in the membrane. These results may provide novel early targets for therapies aimed at regulating the Fc gamma RIIB to control Ab responses in autoimmune disease. The Journal of Immunology, 2010, 184: 1977-1989.