Image_7_Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation.tif
Antigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. We previously showed that actin-mediated B-cell contraction on Ag-presenting surfaces negatively regulates BCR signaling. Non-muscle myosin II (NMII), an actin motor, is involved in B-cell development and antibody responses by mediating B-cell migration, cytokinesis, and Ag extraction from Ag-presenting cells. However, whether and how NMII regulates humoral responses through BCR signaling remains elusive. Utilizing a B-cell-specific, partial NMIIA knockout (cIIAKO) mouse model and NMII inhibitors, this study examined the role of NMII in BCR signaling. Upon BCR binding to antibody-coated planar lipid bilayers (PLB), NMIIA was recruited to the B-cell contact membrane and formed a ring-like structure during B-cell contraction. NMII recruitment depended on phosphatidylinositol 5-phosphatase (SHIP1), an inhibitory signaling molecule. NMII inhibition by cIIAKO did not affect B-cell spreading on PLB but delayed B-cell contraction and altered BCR clustering. Surface BCR “cap” formation induced by soluble stimulation was enhanced in cIIAKO B-cells. Notably, NMII inhibition by cIIAKO and inhibitors up-regulated BCR signaling in response to both surface-associated and soluble stimulation, increasing phosphorylated tyrosine, CD79a, BLNK, and Erk and decreasing phosphorylated SHIP1. While cIIAKO did not affect B-cell development, the number of germinal center B-cells was significantly increased in unimmunized cIIAKO mice, compared to control mice. While cIIAKO mice mounted similar antibody responses when compared to control mice upon immunization, the percentages of high-affinity antibodies, Ag-specific germinal center B-cells and isotype switched B-cells were significantly lower in cIIAKO mice than in control mice. Furthermore, autoantibody levels were elevated in cIIAKO mice, compared to control mice. Collectively, our results reveal that NMII exerts a B-cell-intrinsic inhibition on BCR signaling by regulating B-cell membrane contraction and surface BCR clustering, which curtails the activation of non-specific and self-reactive B-cells.
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References
- https://doi.org//10.1146/annurev.immunol.15.1.453
- https://doi.org//10.1016/j.molimm.2004.04.008
- https://doi.org//10.1038/s41590-019-0427-9
- https://doi.org//10.1111/imr.12744
- https://doi.org//10.1146/annurev.immunol.021908.132541
- https://doi.org//10.1007/s11515-013-1272-0
- https://doi.org//10.1007/82_2015_476
- https://doi.org//10.1016/j.coi.2017.03.003
- https://doi.org//10.1038/nature13300
- https://doi.org//10.1126/sciimmunol.aau6598
- https://doi.org//10.1016/j.coi.2017.06.008
- https://doi.org//10.1111/imr.12861
- https://doi.org//10.1038/nature08638
- https://doi.org//10.1016/j.semcancer.2013.09.001
- https://doi.org//10.1038/nri.2017.24
- https://doi.org//10.1007/s12016-017-8609-4
- https://doi.org//10.1111/j.1600-065x.1980.tb00328.x
- https://doi.org//10.1111/j.1600-065X.2008.00583.x
- https://doi.org//10.1146/annurev-immunol-030409-101216
- https://doi.org//10.1038/nri726
- https://doi.org//10.1083/jcb.200802007
- https://doi.org//10.1016/j.coi.2006.03.013
- https://doi.org//10.1126/scisignal.263pt1
- https://doi.org//10.3389/fimmu.2018.00665
- https://doi.org//10.1126/science.1071546
- https://doi.org//10.1146/annurev.immunol.021908.132649
- https://doi.org//10.1101/cshperspect.a002360
- https://doi.org//10.1111/imr.12113
- https://doi.org//10.1038/nri.2017.67
- https://doi.org//10.1016/j.immuni.2009.12.005
- https://doi.org//10.4049/jimmunol.1102233
- https://doi.org//10.4049/jimmunol.1103065
- https://doi.org//10.1126/science.1123940
- https://doi.org//10.4049/jimmunol.1100157
- https://doi.org//10.1371/journal.pbio.1001704
- https://doi.org//10.1073/pnas.1321971111
- https://doi.org//10.1038/nrm2786
- https://doi.org//10.1016/j.celrep.2018.04.087
- https://doi.org//10.1126/science.1237572
- https://doi.org//10.1038/ni.3458
- https://doi.org//10.1083/jcb.201607064
- https://doi.org//10.7554/eLife.66984
- https://doi.org//10.3791/1026
- https://doi.org//10.1007/s10974-004-6060-7
- https://doi.org//10.2174/092986709787846569
- https://doi.org//10.1074/jbc.M702731200
- https://doi.org//10.1186/ar3927
- https://doi.org//10.1182/blood-2011-06-358853
- https://doi.org//10.1242/dmm.022103
- https://doi.org//10.4049/jimmunol.170.12.6099
- https://doi.org//10.1016/j.molimm.2018.07.018
- https://doi.org//10.1007/82_2015_477
- https://doi.org//10.1113/JP274395
- https://doi.org//10.1615/CritRevImmunol.2019029595
- https://doi.org//10.1126/scisignal.aai9192
- https://doi.org//10.1111/imr.12396
- https://doi.org//10.1016/j.coi.2019.11.001
- https://doi.org//10.1111/j.1600-065X.2012.01118.x
- https://doi.org//10.1016/j.tcb.2005.05.004
- https://doi.org//10.1016/j.abb.2011.03.002
- https://doi.org//10.1002/eji.201242809
- https://doi.org//10.1016/s0092-8674%2800%2980337-2
- https://doi.org//10.1016/s1074-7613%2800%2980555-5
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- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity