Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR
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-mediate...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00415/full |
| _version_ | 1818931230710693888 |
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| author | Niels J. M. Verstegen Niels J. M. Verstegen Peter-Paul A. Unger Julia Z. Walker Benoit P. Nicolet Tineke Jorritsma Jos van Rijssel Robbert M. Spaapen Jelle de Wit Jaap D. van Buul Anja ten Brinke S. Marieke van Ham S. Marieke van Ham |
| author_facet | Niels J. M. Verstegen Niels J. M. Verstegen Peter-Paul A. Unger Julia Z. Walker Benoit P. Nicolet Tineke Jorritsma Jos van Rijssel Robbert M. Spaapen Jelle de Wit Jaap D. van Buul Anja ten Brinke S. Marieke van Ham S. Marieke van Ham |
| author_sort | Niels J. M. Verstegen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T04:13:18Z |
| format | Article |
| id | doaj.art-5d430dc73d35412da79d6bdd7d01eb74 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T04:13:18Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5d430dc73d35412da79d6bdd7d01eb742022-12-21T19:53:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00415432569Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCRNiels J. M. Verstegen0Niels J. M. Verstegen1Peter-Paul A. Unger2Julia Z. Walker3Benoit P. Nicolet4Tineke Jorritsma5Jos van Rijssel6Robbert M. Spaapen7Jelle de Wit8Jaap D. van Buul9Anja ten Brinke10S. Marieke van Ham11S. Marieke van Ham12Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsSynthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsSwammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, NetherlandsGrowing 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.00415/fullB cellCRISPRinternalizationsignaling pathwaylarge antigen-containing particle |
| spellingShingle | Niels J. M. Verstegen Niels J. M. Verstegen Peter-Paul A. Unger Julia Z. Walker Benoit P. Nicolet Tineke Jorritsma Jos van Rijssel Robbert M. Spaapen Jelle de Wit Jaap D. van Buul Anja ten Brinke S. Marieke van Ham S. Marieke van Ham Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR Frontiers in Immunology B cell CRISPR internalization signaling pathway large antigen-containing particle |
| title | Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR |
| title_full | Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR |
| title_fullStr | Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR |
| title_full_unstemmed | Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR |
| title_short | Human B Cells Engage the NCK/PI3K/RAC1 Axis to Internalize Large Particles via the IgM-BCR |
| title_sort | human b cells engage the nck pi3k rac1 axis to internalize large particles via the igm bcr |
| topic | B cell CRISPR internalization signaling pathway large antigen-containing particle |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00415/full |
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