Antigen Presentation by Dendritic Cells for B Cell Activation

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Antigen Presentation by Dendritic Cells for B Cell Activation Available online at www.sciencedirect.com ScienceDirect Antigen presentation by dendritic cells for B cell activation 1,2 1,2,4 1,2 William R Heath , Yu Kato , Thiago M Steiner and 3 Irina Caminschi B cells are efficiently activated by antigens presented on cell processes. To tailor effective antibody responses, germinal membranes, which provide opportunity for receptor cross- center (GC) reactions are evoked upon initial pathogen linking and antigen capture. The two main cell types implicated encounter, promoting B cell somatic hypermutation and in native antigen presentation to B cells are follicular dendritic isotype switching, eventually yielding long-term, high + cells (FDC), which reside in B cell follicles, and CD169 affinity, antibody-producing plasma cells of the appropriate macrophages, which line the antigen-exposed surfaces of isotype. Because of their potential to cause pathology to the these follicles in both the lymph nodes and the spleen. There is host, antibody production must be carefully regulated, mounting evidence, however, that conventional dendritic cells especially during GC reactions, where somatic hypermuta- (cDC) can also participate in native antigen presentation to tion has the capacity to generate new specificities, poten- B cells. This underappreciated role, largely hidden by the tially against self. One important control mechanism here is simultaneous need for cDC to participate in T cells priming, the B cells requirement for T cell help. Because T cells are appears to be primarily mediated by the type 2 subset of cDC rendered tolerant to self during thymic selection, specifi- (cDC2), but may also be a function of cDC1. Better cities for self are rare and, as a consequence, so is help for B understanding of how cDC participate in B cell priming is likely cells that mutate to autoreactive specificities. to improve our capacity to develop effective humoral vaccines. + To receive CD4 T cell help, B cells must process and present Addresses antigen on MHC II. B cell-mediated antigen presentation is 1 Department of Microbiology and Immunology, The Doherty Institute for also important for the subsequent differentiation of helper T Infection and Immunity, The University of Melbourne, Victoria, 3010, Australia cells into the T follicular helper lineage (Tfh cells), which are 2 Australian Research Council Centre of Excellence in Advanced the crucial subset that provide help within GCs. Upon antigen Molecular Imaging, University of Melbourne, Victoria, 3010, Australia recognition on B cells, Tfh cells deliver various signals includ- 3 Infection and Immunity Program, Monash Biomedicine Discovery ing the soluble factors IL-21 and IL-4, and membrane-bound Institute and Department of Biochemistry and Molecular Biology, signals such as CD40 ligand, which aid B cell survival, Monash University, Clayton, Victoria, 3168, Australia proliferation, and differentiation [1]. Tfh cells must also Corresponding authors: Heath, William R ([email protected]), express the appropriate chemokine receptors, such as Caminschi, Irina ([email protected]) CXCR5, for localization within B cell follicles where they 4 Current address: Division of Vaccine Discovery, La Jolla Institute for provide this help. Eliciting Tfh cell responses is complex but Immunology, La Jola, CA 92037, United States. essentially proceeds in two steps: first, naı¨ve T cells are activated by cDC, which present their cognate antigen in Current Opinion in Immunology 2019, 58:44–52 the context of MHC II and provide costimulatory signals This review comes from a themed issue on Antigen processing through receptors on T cells such as CD28 and ICOS. Then, Edited by Justine D Mintern and Jose A Villadangos these pre-Tfh cells migrate to the T–B border, where they For a complete overview see the Issue and the Editorial recognize antigen presented by antigen-specific B cells, lead- Available online 6th May 2019 ing to full Tfh maturation. Thus, for T-dependent B cell responses, T cells are required to recognize antigen first on https://doi.org/10.1016/j.coi.2019.04.003 DC, then on B cells. As a consequence, preventing DC-driven 0952-7915/Crown Copyright ã 2019 Published by Elsevier Ltd. All + activation of CD4 T cells, effectively blocks T-dependent rights reserved. humoral immunity. This critical requirement for DC in the priming of T cells has largely hidden another potentially important role for DC in promoting humoral immunity, namely, the direct presentation of intact antigen to B cells. This underappreciated function is receiving growing recog- nition and will be discussed in this short review. Introduction Antibodies are the hallmarks of humoral immunity, acting via various heavy chain isotypes to provide a plethora of Membrane antigens activate B cells more immune effector functions, from simple neutralization of effectively than soluble antigens pathogen-infectivity, to opsonization of microbes for To appreciate the potential importance of DC in pre- destruction by cell-mediated or complement-mediated sentation of antigen to B cells, it is first worth revisiting Current Opinion in Immunology 2019, 58:44–52 www.sciencedirect.com Antigen presentation by dendritic cells for B cell activation Heath et al. 45 some old studies that show membrane-bound antigens be bound by Fc receptors (FcR), which may lead to phago- are more effective than soluble antigens at eliciting cytoses, but those captured by FcgRIIb are trafficked B cell responses [2–4]. In studies examining transgenic through non-degradative intracellular compartments and B cell tolerance to H-2K antigens encountered in the recycled as native antigens to the cell surface where they periphery by mature B cells, membrane-bound antigen can be displayed to B cells [8 ]. While the capture and display efficiently deleted antigen-specific B cells whereas sol- of opsonized antigen is well established, other mechanisms uble monovalent antigen was ineffective [2,5]. Similarly, are also operative. For example, the capture of vesicular while membrane-bound hen egg lysozyme (HEL) effec- stomatitis virus (VSV) in the lymph node is independent of tively deleted developing B cells, soluble HEL was only C3 complement or secreted immunoglobulin [9 ]. Although able to induce anergy, presumably because of its weaker the precise mechanism of VSV capture is unknown, an array cross-linking capacity [3]. Examination of the uptake of of cell surface receptors bind microbial components and may various forms of HEL by B cells revealed that B cell contribute to their capture and presentation [10,11]. In this recognition of membrane-bound HEL led to formation vein, for UV-inactivated influenza virus, the C-type lectin of an immunological synapse that resulted in efficient SIGNR1 receptor was shown to be involved in the capture of acquisition of antigen [4]. Importantly, in this system, this virus and its presentation to B cells [12 ]. In humans, the membrane-bound HEL was shown to be several orders closely related C-type lectin, DC-SIGN has been shown to of magnitude more effective than its soluble counterpart interact with multiple pathogens [13], including HIV, where at inducing B cell activation. Thus, membrane-bound it is involved in internalization of intact virus and its recycling antigens provide a strong cross-linking signal that effi- to the cell surface [14]. ciently facilitates both B cell activation and antigen acquisition. In summary, an array of receptors expressed on various cell types may be involved in the capture of opsonized It is interesting to speculate as to why membrane-bound and non-opsonized microbes and their antigens for the antigens have evolved as the preferred antigen source for B presentation to B cells. In this review, we will restrict cells. This may be because B cells are normally bathed in a discussion to primary B cell responses, with a focus on the sea of soluble self-antigens that are best ignored to mini- requirements for initial antigen recognition before GC mize autoimmunity. Alternatively, it may relate to a needto formation, rather than to downstream affinity selection or concentrate antigens for efficient B cell recognition, with secondary responses. membrane association providing the platform for concen- tration. Whatever the reason, membrane-tethered Antigen presentation by FDC and pathogen-derived antigensappear to be superior at evoking macrophages for initiating B cell activation humoral immunity. Membrane-bound antigens may natu- There are two main cell types implicated in presentation rally exist within the pathogen membranes, providing the of antigen to B cells during primary responses: macro- desired multi-arrayed membrane-associated context phages and FDC (Figure 1). Antigens entering the important for B cell activation. Alternatively, pathogen- lymph nodes from the afferent lymphatics first access derived antigen can be captured and concentrated on the the subcapsular sinus (SCS) and if sufficiently small surface of host cells via receptors, for presentationto B cells. (<70 KD) can drain through conduits that supply inter- This latter context appears to be a common mechanism follicular, medullary [15] or follicular [16] regions, or associated with induction of humoral immunity. they can diffuse directly into the follicles through gaps in the floor of the SCS [17,18]. Larger antigens are captured The many ways to provide Ag in a membrane- by macrophages [19,20 ,21 ] and cDC [22] within the + associated form subcapsular sinus (SCS). CD169 SCS macrophages, Given the superior
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