Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR

• Published in: Frontiers in immunology Vol. 10; p. 415
• Main Authors: Verstegen, Niels J. M., Unger, Peter-Paul A., Walker, Julia Z., Nicolet, Benoit P., Jorritsma, Tineke, van Rijssel, Jos, Spaapen, Robbert M., de Wit, Jelle, van Buul, Jaap D., ten Brinke, Anja, van Ham, S. Marieke
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 13.03.2019
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Antigen Presentation - immunology; B cell; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CRISPR; Humans; Immunoglobulin M - immunology; Immunology; internalization; large antigen-containing particle; Lymphocyte Activation - immunology; Oncogene Proteins - immunology; Phagocytosis - immunology; Phosphatidylinositol 3-Kinases - immunology; rac1 GTP-Binding Protein - immunology; Receptors, Antigen, B-Cell - immunology; Signal Transduction - immunology; signaling pathway; signaling pathway; B cell; CRISPR; internalization; large antigen-containing particle
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.00415

Growing evidence indicate that large antigen-containing particles induce potent T cell-dependent high-affinity antibody responses. These responses require large particle internalization after recognition by the B cell receptor (BCR) on B cells. However, the molecular mechanisms governing BCR-mediated internalization remain unclear. Here we use a high-throughput quantitative image analysis approach to discriminate between B cell particle binding and internalization. We systematically show, using small molecule inhibitors, that human B cells require a SYK-dependent IgM-BCR signaling transduction via PI3K to efficiently internalize large anti-IgM-coated particles. IgM-BCR-mediated activation of PI3K involves both the adaptor protein NCK and the co-receptor CD19. Interestingly, we here reveal a strong NCK-dependence without profound requirement of the co-receptor CD19 in B cell responses to large particles. Furthermore, we demonstrate that the IgM-BCR/NCK signaling event facilitates RAC1 activation to promote actin cytoskeleton remodeling necessary for particle engulfment. Thus, we establish NCK/PI3K/RAC1 as an attractive IgM-BCR signaling axis for biological intervention to prevent undesired antibody responses to large particles.