101. Distinct Roles for Bruton's Tyrosine Kinase in B Cell Immune Synapse Formation.
- Author
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Roman-Garcia S, Merino-Cortes SV, Gardeta SR, de Bruijn MJW, Hendriks RW, and Carrasco YR
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Agammaglobulinaemia Tyrosine Kinase genetics, Animals, Antigens metabolism, Benzamides pharmacology, Calcium Signaling, Cell Polarity, Cell Proliferation, Cells, Cultured, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Microtubule-Organizing Center, Mutation genetics, Phospholipase C gamma metabolism, Piperidines, Protein Transport, Pyrazines pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, Receptors, Antigen, B-Cell metabolism, Agammaglobulinaemia Tyrosine Kinase metabolism, B-Lymphocytes immunology, Cell Membrane metabolism, Immunological Synapses metabolism
- Abstract
Bruton's tyrosine kinase (Btk) has a key role in the signaling pathways of receptors essential for the B lymphocyte response. Given its implication in B cell-related immunodeficiencies, leukemias/lymphomas and autoimmunity, Btk is studied intensely and is a target for therapy. Here, using primary B cells from distinct mouse models and the pharmacological inhibitors ibrutinib and acalabrutinib, we report distinct roles for Btk in antigen-triggered immune synapse (IS) formation. Btk recruitment to the plasma membrane regulates the B cell ability to trigger IS formation as well as its appropriate molecular assembly; Btk shuttling/scaffold activities seem more relevant than the kinase function on that. Btk-kinase activity controls antigen accumulation at the IS through the PLCγ2/Ca
2+ axis. Impaired Btk membrane-recruitment or kinase function likewise alters antigen-triggered microtubule-organizing center (MTOC) polarization to the IS, B cell activation and proliferation. Data also show that, for B cell function, IS architecture is as important as the quantity of antigen that accumulates at the synapse.- Published
- 2018
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