In primary humoral responses, B-cell lymphoma 6 (Bcl6) is a master regulator of follicular helper T (TFH) cell differentiation; however, its activation mechanisms and role in memory responses remain unclear. Here we demonstrate that survival of CXCR5+ TFH memory cells, and thus subsequent recall antibody response, require Bcl6 expression. Furthermore, we show that, upon rechallenge with soluble antigen Bcl6 in memory TFH cells is rapidly induced in a dendritic cell-independent manner and that peptide:class II complexes (pMHC) on cognate memory B cells significantly contribute to this induction. Given the previous evidence that antigen-specific B cells residing in the follicles acquire antigens within minutes of injection, our results suggest that memory B cells present antigens to the cognate TFH memory cells, thereby contributing to rapid Bcl6 reexpression and differentiation of the TFH memory cells during humoral memory responses.

•Initial Ca2+ signals from ER are controlled by PLC-γ2 and PI3K pathway.•ER calcium sensors STIM and Orai1 channel are critical component for SOCE.•SOCE in B cells are dispensable for B cell development and antibody responses.•SOCE in B cells is required for BCR-mediated NFAT activation to induce IL-10 production.•STIM-dependent IL-10 production by B cells suppresses the development of autoimmunity.Calcium signals are crucial for diverse cellular functions including adhesion, differentiation, proliferation, effector functions and gene expression. After engagement of the B cell receptor, the intracellular calcium ion (Ca2+) concentration is increased promoting the activation of various signaling cascades. While elevated Ca2+ in the cytosol initially comes from the endoplasmic reticulum (ER), a continuous influx of extracellular Ca2+ is required to maintain the increased level of cytosolic Ca2+. Store-operated Ca2+ entry manages this process, which is regulated by an ER calcium sensor, stromal interaction molecule (STIM). STIM proteins sense changes in the levels of Ca2+ stored within the ER lumen and regulates the Ca2+-release activated Ca2+ channel in the plasma membrane. This review focuses on the signaling pathways leading to Ca2+ influx and the role of Ca2+ signals in B cell functions.

In B cells, changes in intracellular concentration of Ca2+ drive signal transduction to initiate changes in gene expression and various cellular events, including apoptosis and differentiation. B cell receptor engagement causes a transient Ca2+ flux from the endoplasmic reticulum Ca2+ store, followed by a continuous increase in intracellular Ca2+ concentration, mainly resulting from store-operated Ca2+ entry (SOCE). The recent identification of stromal interaction molecule (STIM) and Orai as essential components for SOCE has allowed researchers to probe further the role of Ca2+ signals in B cell biology. Here, we summarize the B cell signaling pathways that lead to SOCE, the role of Ca2+ signals in B cell regulatory function, and how a breakdown in the balance of Ca2+ signals is associated with immune-related disease.

•Original BCR repertoires affect the fate decisions of B cells.•Plasma cell fate is facilitated by higher affinity in both pre-GC and GC responses.•High expression of IRF4 is required for plasma cell differentiation.•Lower affinity GC B cells are preferentially recruited into the memory pool.•Bach2 is an important factor for memory B cell differentiation from GC B cells.Memory B cell generation and antibody production result from a differentiation process that begins when the surface BCR on naïve B cells binds an antigen. How the choice between these fates is tempo-spatially regulated is still obscure, but recent advances have reinforced the concept that the combination of B cell-intrinsic heterogeneity and -extrinsic heterogeneity provided by cells such as T cells is a key determinant. As molecular regulators, the transcription factors IRF4 and Bach2, which participate in these fate choices, have been emerging.

•Survival of long-lived plasma cells depends on both cell-intrinsic programs and extrinsic factors.•Hematopoietic cells provide the survival factors for long-lived plasma cells in the bone marrow.•ZBTB20 is critical for durable antibody responses.Long-lived plasma cells, which mostly reside in the bone marrow have been shown to be vital for protection from recurrent infections. Recent gene-targeting and cell-ablation experiments have solidified the concept that their survival depends on both cell-intrinsic programs and extrinsic factors. The BTB transcription factor ZBTB20, which is expressed at high levels in long-lived plasma cells, is critical for their survival. On the other hand, eosinophils, megakaryocytes and monocytes function to establish a niche for long-lived plasma cells by secreting cytokines and growth factors such as APRIL and IL6.

A chief Ca2+ entry pathway in immune cells is store-operated Ca2+ (SOC) influx, which is triggered by depletion of Ca2+ from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.Graphical AbstractDownload high-res image (308KB)Download full-size imageHighlights► STIM proteins are required for BCR-mediated SOC influx and proliferation ► STIM proteins are dispensable for B cell development and antibody responses ► STIM-mediated NFAT activation induces IL-10 production by B cells ► STIM-dependent IL-10 production by B cells suppresses the development of autoimmunity

B cell receptor (BCR)-mediated tonic signals are important for B cell survival and development. In this issue of Immunity, Treanor et al. (2010) show that triggering of downstream responses is kept in check with BCR immobilization by actin.

•IgG1 tail alone cannot explain robust antibody production•Expression of Bach2 is decreased in IgG1 memory B cells•Repression of Bach2 contributes to robust antibody production•mTOR signaling is involved in Bach2 repressionMemory B cells are essential for generating rapid and robust secondary antibody responses. It has been thought that the unique cytoplasmic domain of IgG causes the prompt activation of antigen-experienced IgG memory B cells. To assess this model, we have generated a mouse containing IgG1 B cells that have never encountered antigen. We found that, upon challenge, antigen-experienced IgG1 memory B cells rapidly differentiated into plasma cells, whereas nonexperienced IgG1 B cells did not, suggesting the importance of the stimulation history. In addition, our results suggest that repression of the Bach2 transcription factor, which results from antigen experience, contributes to predisposition of IgG1 memory B cells to differentiate into plasma cells.

•Plasmablasts predominantly express IL-10 in the dLNS during EAE induction•Plasmablasts prevent dendritic cells from generating pathogenic T cells•Deficiency of plasmablasts in mice develops an exacerbated EAE•Human plasmablasts derived from naive B cells selectively produce IL-10B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.Download high-res image (317KB)Download full-size image