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Live Cell Imaging Reveals that the Inhibitory FcRIIB Destabilizes B Cell Receptor Membrane-Lipid Interactions and Blocks Immune Synapse Formation¹

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

The FcRIIB is a potent regulator of BCR signaling and as such plays a decisive role in controlling autoimmunity. The use of advanced imaging technologies has provided evidence that the earliest events in Ag-induced BCR signaling include the clustering of the BCR, the selective and transient association of the clustered BCR with raft lipids, and the concentration of BCR clusters in an immune synapse. That lipid rafts play a role in FcRIIB’s regulation of BCR signaling was suggested by recent studies showing that a lupus-associated loss of function mutation resulted in the receptor’s exclusion from lipid rafts and the failure to regulate BCR signaling. In this study, we provide evidence from both biochemical analyses and fluorescence resonance energy transfer in conjunction with both confocal and total internal reflection microscopy in living cells that the FcRIIB, when coligated with the BCR, associates with lipid rafts and functions both to destabilize the association of the BCR with raft lipids and to block the subsequent formation of the B cell’s immune synapse. These results define new early targets of FcRIIB inhibitory activity in the Ag-induced B cell activation pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Shiang-Jong Tzeng, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, 12441 Parklawn Drive, Room 213, Rockville, MD 20852. E-mail address: sjtzeng{at}niaid.nih.gov

³ Abbreviations used in this paper: BCR, B-cell receptor; FRET, fluorescence resonance energy transfer; CFP, cyan fluorescent protein; YFP, yellow fluorescence protein; NP, nitrophenyl; NFRET, normalized FRET; FRa, FRET ratio normalized with acceptor; TIRFM, total internal fluorescence reflection microscopy; IC, immune complex.

⁴ The online version of this article contains supplemental material.