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Key Points The terminal differentiation of B cells generates short-lived plasmablasts and long-lived plasma cells, both of which secrete antibodies. B cells and antibody-secreting cells display markedly divergent transcriptomes. Differentiation of antibody-secreting cells from B cells is controlled by a network of antagonistic transcription factors. Despite considerable heterogeneity, a simple probabilistic differentiation process can explain B cell terminal differentiation. Transition from a short-lived plasmablast to a long-lived plasma cell requires homing to the bone marrow niche. The plasma cell niche consists of a stromal component and a proliferation-inducing ligand (APRIL)-expressing haematopoietic cells. The terminal differentiation of antibody-secreting cells is controlled by a network of antagonistic transcription factors and, although it is highly complex, this process can be explained by a simple probabilistic differentiation process. The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.

The process of B cell differentiation into plasma cells involves dramatic cellular reprogramming. Corcoran and colleagues profile the transcriptome of all stages of B cell differentiation through to antibody-secreting plasma cells. When B cells encounter an antigen, they alter their physiological state and anatomical localization and initiate a differentiation process that ultimately produces antibody-secreting cells (ASCs). We have defined the transcriptomes of many mature B cell populations and stages of plasma cell differentiation in mice. We provide a molecular signature of ASCs that highlights the stark transcriptional divide between B cells and plasma cells and enables the demarcation of ASCs on the basis of location and maturity. Changes in gene expression correlated with cell-division history and the acquisition of permissive histone modifications, and they included many regulators that had not been previously implicated in B cell differentiation. These findings both highlight and expand the core program that guides B cell terminal differentiation and the production of antibodies.

Tarlinton and colleagues show that the antiapoptotic protein Mcl1 is essential for plasma cell survival and is induced by BCMA signaling in bone marrow, but not spleen, plasma cells. The long-term survival of plasma cells is entirely dependent on signals derived from their environment. These extrinsic factors presumably induce and sustain the expression of antiapoptotic proteins of the Bcl-2 family. It is uncertain whether there is specificity among Bcl-2 family members in the survival of plasma cells and whether their expression is linked to specific extrinsic factors. We found here that deletion of the gene encoding the antiapoptotic protein Mcl-1 in plasma cells resulted in rapid depletion of this population in vivo . Furthermore, we found that the receptor BCMA was needed to establish high expression of Mcl-1 in bone marrow but not spleen plasma cells and that establishing this survival pathway preceded the component of plasma cell differentiation that depends on the transcriptional repressor Blimp-1. Our results identify a critical role for Mcl-1 in the maintenance of plasma cells.

Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo , using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti-apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers.

Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation. PU.1 and SpiB regulate the expression of many components of the B cell receptor signaling pathway and the receptors for CD40L, BAFF and TLR ligands. Thus, PU.1 and SpiB enable B cells to appropriately respond to environmental cues. Although important for early development, PU.1 is dispensable for mature B cell function, possibly owing to compensation by the related transcription factor SpiB. Here the authors show PU.1 and SpiB are collectively required for humoral immunity, through regulation of germinal centre formation and plasma cell differentiation.

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation. How IL-21 functions during development of high affinity antibody in germinal centres (GC) is not fully known. Here using a cell cycle reporter mouse, the authors show that IL-21 promotes cell cycle progression within the GC light zone and enables release from the G1 cell cycle stage.

Bcl6 (B‐cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T‐cell‐dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B‐cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post‐transcriptional levels, and in particular a strong signal through the B‐cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B‐cell receptor (BCR) signal, but that the T‐cell‐derived cytokines interleukin 4 (IL4) and IL21 counteract BCR‐mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B‐cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T‐follicular helper cytokines on Bcl6 regulation.

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by increased sensitivity to self-antigens, auto-antibody production, and systemic inflammation. B cells have been implicated in disease progression and as such represent an attractive therapeutic target. Lyn is a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B cells as well as other hematopoietic cells. Its role in initiating negative signaling cascades is especially critical as exemplified by Lyn mice developing an SLE-like disease with plasma cell hyperplasia, underscoring the importance of tightly regulating signaling within B cells. This review highlights recent advances in our understanding of the function of the Src family tyrosine kinase Lyn in B lymphocytes and its contribution to positive and negative signaling pathways that are dysregulated in autoimmunity.

Lymphocyte survival during immune responses is controlled by the relative expression of pro- and anti-apoptotic molecules, regulating the magnitude, quality, and duration of the response. We investigated the consequences of deleting genes encoding the anti-apoptotic molecules Mcl1 and Bcl2l1 (Bcl-xL) from B cells using an inducible system synchronized with expression of activation-induced cytidine deaminase (Aicda) after immunization. This revealed Mcl1 and not Bcl2l1 to be indispensable for the formation and persistence of germinal centers (GCs). Limiting Mcl1 expression reduced the magnitude of the GC response with an equivalent, but not greater, effect on memory B cell formation and no effect on persistence. Our results identify Mcl1 as the main anti-apoptotic regulator of activated B cell survival and suggest distinct mechanisms controlling survival of GC and memory B cells.

FasL's non-apoptotic functions The transmembrane protein known as FasL (Fas ligand) is a member of the tumour necrosis factor family with an important role in immune regulation. The binding of FasL with its receptor induces apoptosis, but it has not been clear how important cell death is in FasL's cellular functions. Experiments using gene-targeted mice that either lack secreted FasL but express normal levels of membrane-bound FasL or, that lack membrane-bound FasL but can still produce secreted FasL, show that soluble FasL promotes autoimmunity and tumorigenesis through mechanisms that do not involve apoptosis. Fas ligand (FasL) and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding, but it is unclear what the respective roles of these secreted and membrane-bound forms are. Gene-targeted mice that selectively lack either secreted FasL or membrane-bound FasL are now generated, shedding light on this problem. Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses 1 , 2 , 3 and prevention of autoimmunity 4 , 5 . Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice 6 , 7 and humans 8 , 9 . FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding 10 , 11 . Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL ( FasL Δs/Δs ) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL ( FasL Δm/Δm ) could not kill cells through Fas activation. FasL Δm/Δm mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL gld/gld mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL Δm/Δm mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL gld/gld mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.