Antigen-induced oligomerization of the B cell receptor is an early target of Fc gamma RIIB inhibition.
The FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB, but relies on the rapid and sustained association of FcgammaRIIB with raft lipids in the membrane. These results may provide novel early targets for therapies aimed at regulating the FcgammaRIIB to control Ab responses in autoimmune disease.
Liu
Wanli
W
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852,USA.
Won Sohn
Hae
H
Tolar
Pavel
P
Meckel
Tobias
T
Pierce
Susan K
SK
D000595:Amino Acid Sequence; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism / Q000502:physiology*; D000941:Antigens / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D010766:Phosphorylation / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D011940:Receptor Aggregation / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D017452:Receptors, IgG / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
D000936:Antigen-Antibody Complex; D000941:Antigens; C080571:Fc gamma receptor IIB; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases