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Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and B cell activation.

ABSTRACT: When B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells, this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodeling in B cell responses to APC-bound antigens.

SUBMITTER: Bolger-Munro M

PROVIDER: S-EPMC6591008 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and B cell activation.

Bolger-Munro Madison M Choi Kate K Scurll Joshua M JM Abraham Libin L Chappell Rhys S RS Sheen Duke D Dang-Lawson May M Wu Xufeng X Priatel John J JJ Coombs Daniel D Hammer John A JA Gold Michael R MR

eLife 20190603

When B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends ...[more]

PMID: 31157616

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Project description:T lymphocyte recognition of antigenic peptides on the surface of antigen-presenting cells (APC) leads to immune synapse formation (IS). By analogy with the nervous synapse, this cell-cell communication model requires the formation of highly organized structures that delimit an active zone of membrane traffic. For T cells to connect antigen recognition with the biological response, receptors and signaling proteins must be recycled. Sorting nexin 27 (SNX27) is an endosomal protein best known for its role in recycling PDZ (PSD95, Dlg1, ZO-1)-interacting neuronal proteins via the retromer transport machinery. Alteration of this sorting pathway leads to neurodegeneration and is associated to Down syndrome, Alzheimer’s and Parkinson’s diseases. In T lymphocytes, SNX27 interacts with diacylglycerol kinase zeta (DGKz), which provides a mechanistic link between diacylglycerol metabolism and membrane trafficking. Following antigen recognition, SNX27-positive endosomes polarize to the IS and a PDZ-dependent SNX27 pool accumulates at the cell-cell contact area. To test for additional SNX27 functions, we carried out proteomic analysis of the SNX27 interactome purified from T cells in contact with APC, and identified SNX27 interaction with the retromer and with members of the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) complex. This finding indicates the conserved nature of the SNX27/WASH/retromer complex in hematopoietic cells and suggests similarity between neurological diseases and abnormal immune/inflammatory responses. We also found PDZ-dependent SNX27 cargoes, including modulators of cytoskeletal reorganization such as zona occludens-2 (ZO-2). ZO-2, a cytosolic component of epithelial cell-cell junctions, localized to the IS, and SNX27 silencing affected ZO-2 stability at the synapse. This study broadens our knowledge of SNX27 function in T lymphocytes, and suggests that pathways that delimit polarized structures in epithelial systems also participate in IS regulation.

Dataset Information

Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and B cell activation.

Publications

Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and B cell activation.

Similar Datasets

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