Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852,USA.
J Immunol. 2010 Feb 15;184(4):1977-89. doi: 10.4049/jimmunol.0902334. Epub 2010 Jan 18.
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.
FcγRIIB 是一种有效的抑制性共受体，可阻断 BCR 信号转导对免疫复合物的反应，因此在调节 Ab 反应中起着决定性的作用。最近应用高分辨率活细胞成像技术研究 B 细胞，为 Ag 结合后几秒钟内启动 BCR 信号转导的最早事件提供了新的分子细节。在这项研究中，我们报告了当通过免疫复合物交联到 BCR 时，FcγRIIB 与 BCR 在微观簇中共定位，并阻断了启动 BCR 信号转导的最早事件，包括这些簇内 BCR 的寡聚化、BCR 向这些簇的主动募集，以及由此产生的扩展和收缩反应。荧光共振能量转移分析表明，阻断这些早期事件可能不需要 BCR 和 FcγRIIB 细胞质结构域的分子接近，但依赖于 FcγRIIB 与膜中筏脂质的快速和持续关联。这些结果可能为旨在调节 FcγRIIB 以控制自身免疫性疾病中 Ab 反应的治疗提供新的早期靶点。
