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J Immunol. 2014 Jun 1;192(11):5179-91. doi: 10.4049/jimmunol.1400101. Epub 2014 Apr 30.

Through an ITIM-independent mechanism the FcγRIIB blocks B cell activation by disrupting the colocalized microclustering of the B cell receptor and CD19.

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  • 1Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China;
  • 2Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, 100084, China;
  • 3Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China;
  • 4Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China;
  • 5Laboratory of Immunogenetics Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and.
  • 6Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, 100084, China; liuwanli@biomed.tsinghua.edu.cn wenjzheng@gmail.com chenyh@mail.tsinghua.edu.cn.
  • 7Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China; liuwanli@biomed.tsinghua.edu.cn wenjzheng@gmail.com chenyh@mail.tsinghua.edu.cn.
  • 8Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Collaborative Innovation Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China liuwanli@biomed.tsinghua.edu.cn wenjzheng@gmail.com chenyh@mail.tsinghua.edu.cn.

Abstract

B cell activation is regulated through the interplay of the BCR with the inhibitory coreceptor FcγRIIB and the activating coreceptor CD19. Recent studies suggest that Ag-driven BCR microclusters are efficiently converted to a signaling active state on colocalization with CD19 microclusters. Using total internal reflection fluorescence microscopy-based, high-resolution, high-speed live-cell and molecule imaging approaches, we show that when co-ligated to the BCR, the FcγRIIB can inhibit B cell activation by blocking the colocalization of BCR and CD19 microclusters within the B cell immunological synapse. Remarkably, this inhibitory function of FcγRIIB is dependent not on its well-characterized ITIM-containing cytoplasmic domain, but its transmembrane domain. Indeed, human primary B cells from systemic lupus erythematosus patients homozygous for gene encoding the loss-of-function transmembrane domain mutant FcγRIIB-I232T fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule p-PI3K to membrane proximal signalosome. This inhibitory function of FcγRIIB in impairing the spatial-temporal colocalization of BCR and CD19 microclusters in the B cell immunological synapse may help explain the hyper-reactive features of systemic lupus erythematosus patient B cells in reported studies. These observations may also provide new targets for therapies for systemic autoimmune disease.

[PubMed - indexed for MEDLINE]
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