B cells form immunological synapses upon engagement of their B cell receptor (BCR) with antigen that is exposed at the surface of specialized presenting cells. Synapse formation promotes the extraction and the processing of immobilized antigens for presentation on MHC class II molecules to primed CD4+ T cells. This is required for B cells to form germinal centres and to produce high-affinity antibodies.
The formation of an immunological synapse is associated with a rapid actin-dependent membrane spreading response at the antigen contact site, which increases the amount of BCR–antigen encounters and is required for the formation of signalling microclusters that contain recruited antigens and signalling molecules. This is followed by a contraction phase that is mediated by both the actin and microtubule cytoskeleton, in which antigen-containing microclusters are concentrated at the centre of the synapse by the microtubule motor dynein.
B cells rapidly relocalize their microtubule-organizing centre (MTOC), together with their MHC class II-containing lysosomes, at the site of antigen encounter — a process that relies on conserved polarity proteins, including the small GTPase cell division control protein 42 (CDC42) and its effector protein atypical protein kinase C type-ζ (PKCζ). Polarized lysosomes are locally secreted, which facilitates synapse acidification and the extracellular release of hydrolases that promote extraction of the immobilized antigens.
Impairment of MTOC and lysosome polarization via CDC42 or PKCζ silencing compromises antigen processing and presentation to T cells. This highlights how MTOC-dependent exocytosis of secretory lysosomes at the immunological synapse couples antigen extraction to its processing and is crucial for B cells to acquire their antigen presentation function.
B cells can represent interesting models to study cell polarity, as they acquire polarized phenotypes during different stages of their activation or when scanning for antigens. They acquire these phenotypes through the formation of immunological synapses or as they asymmetrically divide after antigen uptake. Therefore, proteins that regulate B cell polarity are valuable candidates to modulate B cell responses in vivo.
B cells are key components of the adaptive immune response. Their differentiation into either specific memory B cells or antibody-secreting plasma cells is a consequence of activation steps that involve the processing and presentation of antigens. The engagement of B cell receptors by surface-tethered antigens leads to the formation of an immunological synapse that coordinates cell signalling events and that promotes antigen uptake for presentation on MHC class II molecules. In this Review, we discuss membrane trafficking and the associated molecular mechanisms that are involved in antigen extraction and processing at the B cell synapse, and we highlight how B cells use cell polarity to coordinate the complex events that ultimately lead to efficient humoral responses.
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The authors kindly thank C. Hivroz, Y. R. Carrasco, D. Obino and D. Lankar for discussions and critical reading of the manuscript. This work was funded by grants from the European Research Council to A.-M.L.-D. and the L'Agence nationale de la recherche Jeunes Chercheuses et Jeunes Chercheurs programme to P.P.
The authors declare no competing financial interests.
- Immunological synapse
The interface between an antigen-presenting cell and a lymphocyte. The hallmark of this structure comprises two concentric regions: one region that is referred to as the central supramolecular activation cluster (cSMAC), where immune receptors are enriched, and another region that is referred to as the peripheral SMAC (pSMAC), which contains adhesion molecules such as lymphocyte function-associated 1 (LFA1) bound to its ligand intercellular adhesion molecule 1 (ICAM1).
- Cell polarity
The asymmetric organization of both functional and structural cell components, which are crucial to coordinate diverse biological functions ranging from directional cell migration and asymmetric cell division to the maintenance of tissue integrity.
- CXC-chemokine ligand 13
(CXCL13). A chemokine belonging to the CXC-chemokine family that functions as a chemoattractant for B cells by binding to CXC-chemokine receptor 5 (CXCR5).
- Lymphocyte function-associated antigen 1
(LFA1). An integrin that is formed by the α-integrin (also known as CD11a) and β-integrin (also known as CD18) chains, It is present in diverse cell types of the immune system, such as lymphocytes, macrophages and neutrophils. LFA1 binds to its ligand intercellular adhesion molecule 1 (ICAM1), which is present on the cell surface of antigen-presenting cells. In B cells, it promotes cell adhesion and antigen gathering during immunological synapse formation, thereby facilitating B cell activation.
Motile adhesive interactions between lymphocytes and antigen-presenting cells. They differ from synapses because the interactions can be transitory.
- ERM proteins
A family of three closely related proteins formed by ezrin, radixin and moesin that connect actin filaments with the plasma membrane. They possess a FERM (protein 4.1, ezrin, radixin and moesin) domain that mediates interactions with proteins in the plasma membrane and a charged carboxyl terminus that interacts with actin filaments.
- Stochastic simulations
A system of particles can be described by its equations of motion. In a system that is subject to thermal fluctuations it is necessary to include a stochastic (random) term that accounts for these fluctuations. By using stochastic simulations a numerical integration of these equations can be generated. Quantities that are experimentally measurable are obtained by averaging several realizations of the process.
- Microtubule organizing centre
(MTOC; also known as the centrosome in animal cells). A major site of microtubule nucleation that is enriched in α-tubulin. This dynamic structure organizes the mitotic and meiotic spindle and basal bodies that are associated with cilia.
The central degradative compartments of the cell. The lysosomes contain an acidic pH (4.6–5.0) and they are where lysosomal hydrolases are concentrated.
- Atypical protein kinase C ζ-type
(PKCζ). An atypical member of the PKC family that does not require either calcium or diacylglycerol for its activation. It associates with partitioning defective 3 (PAR3) to regulate cell polarity in diverse cell types.
- Cell division control protein 42
(CDC42). A RHO-GTPase that controls diverse cellular functions including cell morphology, migration and cell division. By interacting with Wiskott–Aldrich syndrome protein (WASP), CDC42 regulates actin polymerization.
- Asymmetric cell division
A cell division in which the organelles and proteins do not distribute equally, giving rise to two daughter cells with different properties and fates. This is required for cell specialization and mainly relies on asymmetry in the spindle position during the prophase stage of mitosis. Notably, stem cells can divide asymmetrically to give rise to two distinct daughter cells: one cell that is a copy of themselves and one cell that is programmed to differentiate into another cell type.
- Total internal reflection fluorescence microscopy
(TIRFM). A fluorescence microscopy technique that involves illuminating and observing a thin layer of the specimen (about 200 nm) close to the cover slip using an 'evanescent wave' (which is formed when a laser encounters the glass surface above the critical angle in such a way that it is 'totally reflected'). It combines the speed and the resolution of the usual fluorescence microscopy (being an example of widefield microscopy) with the possibility of excluding excitation and emission from unwanted planes, providing a high signal to noise ratio.
- Beige mice
Members of a mouse strain typified by beige hair that carry the lysosomal trafficking regulator (Lyst) mutation.These mice have an autosomal recessive disorder that is characterized by hypopigmentation and immune cell dysfunction. Beige mouse abnormalities result from aberrant lysosomal trafficking and are similar to those of patients with Chediak–Higashi syndrome.
Protrusion of the plasma membrane that forms at the rear end of migrating cells.
Dynamic actin-rich filamentous protrusions that extend from cells.
- Symmetry breaking
The process by which a system switches from a disordered or a uniform state to a state in which an ordered shape, direction or pattern is established; for example, proteins that are normally uniformly distributed will concentrate at a single spot after receiving a certain stimulus.
The capacity of cells to sense mechanical stimuli, such as deformation of the membrane, the cortex, the nucleus and other structures, or to sense changes in the adhesive properties of the substrate.
- Membrane tension
A measure of how stretched the cell membrane is to compensate for the osmotic pressure of the cytoplasm. It can be modified by changing the osmotic pressure of the medium and can be measured by micromanipulation techniques measuring the force necessary to pull tubes of membrane.
- Partitioning defective 3
(PAR3). Together with PAR6 these proteins form the PAR polarity complex and are both scaffolding proteins that are implicated in cell polarity. PAR3 and PAR6 bind to each other via their PDZ (PSD95, DLGA and ZO1 homology) domains. They localize at the plasma membrane via atypical protein kinase C ζ-type, cell division control protein 42 (bound to PAR6) or via their PDZ domains.
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Yuseff, MI., Pierobon, P., Reversat, A. et al. How B cells capture, process and present antigens: a crucial role for cell polarity. Nat Rev Immunol 13, 475–486 (2013). https://doi.org/10.1038/nri3469
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