Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed ...by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation. Infection responses range from GC responses that persist for months to persistent EF responses with dominant suppression of GCs. Here, we review the current understanding of the functional output of EF and GC responses and the molecular switches promoting them. We discuss the signals that regulate the magnitude and duration of these responses, and outline gaps in knowledge and important areas of inquiry. Understanding such molecular switches will be critical for vaccine development, interpretation of vaccine efficacy and the treatment for autoimmune diseases.
Memory B Cells of Mice and Humans Weisel, Florian; Shlomchik, Mark
Annual review of immunology,
04/2017, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We comprehensively review memory B cells (MBCs), covering the definition of MBCs and their identities and subsets, how MBCs are generated, where they are localized, how they are maintained, and how ...they are reactivated. Whereas naive B cells adopt multiple fates upon stimulation, MBCs are more restricted in their responses. Evolving work reveals that the MBC compartment in mice and humans consists of distinct subpopulations with differing effector functions. We discuss the various approaches to define subsets and subset-specific roles. A major theme is the need to both deliver faster effector function upon reexposure and readapt to antigenically variant pathogens while avoiding burnout, which would be the result if all MBCs generated only terminal effector function. We discuss cell-intrinsic differences in gene expression and signaling that underlie differences in function between MBCs and naive B cells and among MBC subsets and how this leads to memory responses.
Positive selection of germinal center (GC) B cells is driven by B cell receptor (BCR) affinity and requires help from follicular T helper cells. The transcription factors c-Myc and Foxo1 are critical ...for GC B cell selection and survival. However, how different affinity-related signaling events control these transcription factors in a manner that links to selection is unknown. Here we showed that GC B cells reprogram CD40 and BCR signaling to transduce via NF-κB and Foxo1, respectively, whereas naive B cells propagate both signals downstream of either receptor. Although either BCR or CD40 ligation induced c-Myc in naive B cells, both signals were required to highly induce c-Myc, a critical mediator of GC B cell survival and cell cycle reentry. Thus, GC B cells rewire their signaling to enhance selection stringency via a requirement for both antigen receptor- and T cell-mediated signals to induce mediators of positive selection.
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•In GC B cells, CD40 signals via NF-κB but not PI3K, while BCR does not activate NF-κB•Weak BCR signals in GC B cells propagate to Akt-dependent phosphorylation of Foxo1•In GC B cells, both CD40 and BCR signals are required to synergistically induce c-Myc•Combined CD40 and BCR signals induce p-S6 in GC B cells, permitting cell cycle entry
Luo et al. show that CD40 and BCR signaling in GC B cells is rewired to control very different pathways, and both signals are required for optimal induction of c-Myc, suggesting a mechanism of signaling-directed positive selection of GC B cells.
A hallmark of adaptive immune responses is the generation of long‐lived protection after primary exposure to a pathogen. In humoral responses, this protection stems from a combination of sustained ...antibody titers and long‐lived memory B cells (MBCs), with the former deriving from long‐lived plasma cells (PCs). Both types of cell are thought to primarily derive from the germinal center (GC), a unique structure that forms during the immune response to many types of antigenic stimuli. GCs are seeded by antigen‐specific B and T cells that were previously activated in the early stages of the response. The GC does not directly or immediately generate effector function; rather, it is a site of intense B‐cell proliferation and cell death. GC B cells undergo both somatic hypermutation and isotype switch, and a Darwinian process very efficiently selects B cells with higher fitness for survival and expansion. GC B cells adopt a unique activation and transcriptional state, and the cells become poised to differentiate to either MBCs or PCs. Despite this general understanding of the events in the GC, the mechanisms that control both affinity selection as well as differentiation have not been well worked out. In this review, we address what is known about what determines whether GC B cells become MBCs or PCs. This is discussed in the broader context of the origins of both cell types, whether from the GC or potentially other sources. We present a model encompassing recent data from several laboratories including our own that suggests that the GC undergoes a temporal switch that alters the nature of its output from MBCs to PCs as the response progresses. We will discuss B‐cell receptor signaling in the GC as it relates to potential mechanisms for affinity‐based selection during the reaction.
There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we ...found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.
•Long-lived memory B cells are made predominantly in the early germinal center (GC)•Long-lived bone-marrow-resident plasma cells are made very late in the GC response•Subsets of memory B cells are also produced in a temporal order•A substantial fraction of long-lived IgM memory B cells are made prior to GC onset
Generation of memory B and plasma cells is critical for protective immunity. Shlomchik and colleagues demonstrate that the B cell response shifts dramatically from generation of memory B cells at early time points to that of long-lived, bone-marrow-resident plasma cells at late time points.
Summary
Germinal centers (GC) are sites of rapid B‐cell proliferation in response to certain types of immunization. They arise in about 1 week and can persist for several months. In GCs, B cells ...differentiate in a unique way and begin to undergo somatic mutation of the Ig V regions at a high rate. GC B cells (GCBC) thus undergo clonal diversification that can affect the affinity of the newly mutant B‐cell receptor (BCR) for its driving antigen. Through processes that are still poorly understood, GCBC with higher affinity are selectively expanded while those with mutations that inactivate the BCR are lost. In addition, at various times during the extended GC reaction, some GCBC undergo differentiation into either long‐lived memory B cells (MBC) or plasma cells. The cellular and molecular signals that govern these fate decisions are not well‐understood, but are an active area of research in multiple laboratories. In this review, we cover both the history of this field and focus on recent work that has helped to elucidate the signals and molecules, such as key transcription factors, that coordinate both positive selection as well as differentiation of GCBC.
B cells are essential for the development and pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells are typically thought of as sources of autoantibody, but their ...most important pathogenetic roles may be to present autoantigens to T cells and to secrete proinflammatory cytokines. A rate-limiting step in the genesis of autoimmunity then is the activation of autoreactive B cells. Here, mechanisms are discussed that normally prevent such activation and how they break down during disease. Integrating classic work with recent insights, emphasis is placed on efforts to pinpoint the precursor cells for autoantibody-secreting cells and the unique stimuli and pathways by which they are activated.
Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types ...contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Faslpr mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
► B cell-intrinsic MyD88 signaling is absolutely required for ANA formation ► Nephrotoxic T cells are controlled by B cell- but not DC-expressed MyD88 ► Dermatitis development is strongly dependent on MyD88 in DCs ► DC-intrinsic MyD88 signals impair B cell lymphoiesis leading to B cell lymphopenia
The B cell response to Salmonella typhimurium (STm) occurs massively at extrafollicular sites, without notable germinal centers (GCs). Little is known in terms of its specificity. To expand the ...knowledge of antigen targets, we screened plasmablast (PB)-derived monoclonal antibodies (mAbs) for Salmonella specificity, using ELISA, flow cytometry, and antigen microarray. Only a small fraction (0.5%–2%) of the response appeared to be Salmonella-specific. Yet, infection of mice with limited B cell receptor (BCR) repertoires impaired the response, suggesting that BCR specificity was important. We showed, using laser microdissection, that somatic hypermutation (SHM) occurred efficiently at extrafollicular sites leading to affinity maturation that in turn led to detectable STm Ag-binding. These results suggest a revised vision of how clonal selection and affinity maturation operate in response to Salmonella. Clonal selection initially is promiscuous, activating cells with virtually undetectable affinity, yet SHM and selection occur during the extrafollicular response yielding higher affinity, detectable antibodies.
•Salmonella (STm) induces a large plasmablast response that is seemingly non-specific•The response is actually specific with affinities that are too low to detect•Extrafollicular SHM leads to affinity maturation and detectable affinities•The STm response differs markedly from the classical GC response to model antigens
B cell responses to Salmonella proceed via extrafollicular rather than germinal center pathways. Shlomchik and colleagues show that such responses are characterized by promiscuous, yet specific B cell activation, followed by extrafollicular somatic hypermutation, affinity maturation, and isotype switch.
Memory is the defining feature of the adaptive immune system. Humoral immune memory is largely though not exclusively generated in the germinal center (GC), which spawns long-lived plasma cells that ...support ongoing serum antibody titers as well as "memory B cells" (MBCs) that persist in the immune host at expanded frequencies. Upon reencounter with antigen, these MBCs are reactivated and potentially can contribute to protection by further expansion, rapid differentiation to antibody-forming cells, and/or reseeding of a new round of GCs along with somatic V region mutation and selection. Here I will discuss what controls these various potential fates of MBCs and the functional significance of different types of MBC reactivation.
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