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Influenza is one of the best examples of highly mutable viruses that are able to escape immune surveillance. Indeed, in response to influenza seasonal infection or vaccination, the majority of the induced antibodies are strain‐specific. Current vaccine against the seasonal strains with the strategy of surveillance‐prediction‐vaccine does not cover an unmet virus strain leading to pandemic. Recently, antibodies targeting conserved epitopes on the hemagglutinin (HA) protein have been identified, albeit rarely, and they often showed broad protection. These antibody discoveries have brought the feasibility to develop a universal vaccine. Most of these antibodies bind the HA stem domain and accumulate in the memory B cell compartment. Broadly reactive stem‐biased memory responses were induced by infection with antigenically divergent influenza strains and were able to eradicate these viruses, together indicating the importance of generating memory B cells expressing high‐quality anti‐stem antibodies. Here, we emphasize recent progress in our understanding of how such memory B cells can be generated and discuss how these advances may be relevant to the quest for a universal influenza vaccine.

Germinal centers (GCs) are formed in secondary lymphoid tissues upon immunization with T-dependent antigens. In GCs, somatic hypermutation generates B cells with increased antibody affinity and these high-affinity B cells preferentially differentiate into plasma cells, which home to bone marrow and confer long-lived humoral immunity. Recent studies have shed new light on the cellular and molecular basis for initiating the transition from a GC B cell to a plasma cell. Here, we review recent progress in our understanding of how plasma cell generation during the GC reaction is regulated for inducing effective long-term protective immunity and for preventing harmful autoimmunity.

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells act as a first line of defense against reinfection ("constitutive humoral memory"). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies ("reactive humoral memory"), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). However, in the case of re-infection with similar but different strains of viruses, or in response to viral escape mutants, the reactive humoral memory plays a crucial role. Here, we review recent progress in our understanding of how memory B cells are generated in the pre-GC stage and during the GC reaction, and how these memory B cells are robustly reactivated with the help of memory Tfh cells to generate the secondary antibody response. In addition, we discuss how these advances may be relevant to the quest for a vaccine that can induce broadly reactive antibodies against influenza and HIV.

Memory antibody responses are typically seen to T-cell-dependent antigens and are characterized by the rapid production of high titers of high-affinity antigen-specific antibody. The hallmark of T-cell-dependent memory B cells is their expression of a somatically mutated, isotype-switched B-cell antigen receptor, features that are mainly generated in germinal centers. Classical studies have focused on isotype-switched memory B cells (mainly IgG isotype) and demonstrated their unique intrinsic properties in terms of localization and responsiveness to antigen re-exposure. However, recent advances in monitoring antigen-experienced B cells have revealed the considerable heterogeneity of memory B cells, which include unswitched IgM(+) and/or unmutated memory B cells. The IgM and IgG type memory B cells reside in distinct locations and appear to possess distinct origins and effector functions, together orchestrating humoral memory responses.

The transcription factor nuclear factor-kappaB (NF-kappaB) contributes to many events in the immune system. Characterization of NF-kappaB has facilitated our understanding of immune cell differentiation, survival, proliferation, and effector functions. Intense research continues to elucidate the role of NF-kappaB, which is shared in several receptor signaling pathways, such as Toll-like receptors, the tumor necrosis factor receptor, and antigen receptors. The specificity of cellular responses emanating from stimulation of these receptors is determined by post-translational modification, or 'fine tuning', which regulates spatiotemporal dynamics of downstream signaling. Understanding the fine tuning mechanisms of NF-kappaB activation is crucial for insights into biological regulation and for understanding how cellular signaling pathways are tightly regulated to guide different cell fates. In this review, we focus on recent advances that illuminate the fine tuning mechanisms of NF-kappaB activation by BCR signaling and have increased our comprehension of complex signal systems.

Gene-targeting experiments have highlighted the importance of the intracellular protein tyrosine kinases, Lyn, Syk, and Btk, in B-cell receptor-mediated phospholipase C gamma 2 and phosphoinositide 3-kinase activation. In linking such tyrosine kinases with effector enzymes, an important role has emerged for adapter molecules. Adapter proteins nucleate formation of distinct signaling complexes in a specific location within the cell and facilitate the interaction between these signaling components in this particular subcellular compartment, which, in turn, contribute to the qualitative and quantitative control of B-cell signaling.

Memory antibody responses are typically seen to T-cell-dependent antigens and are characterized by the rapid production of high titers of high-affinity antigen-specific antibody. The hallmark of T-cell-dependent memory B cells is their expression of a somatically mutated, isotype-switched B-cell antigen receptor, features that are mainly generated in germinal centers. Classical studies have focused on isotype-switched memory B cells (mainly IgG isotype) and demonstrated their unique intrinsic properties in terms of localization and responsiveness to antigen re-exposure. However, recent advances in monitoring antigen-experienced B cells have revealed the considerable heterogeneity of memory B cells, which include unswitched IgM(+) and/or unmutated memory B cells. The IgM and IgG type memory B cells reside in distinct locations and appear to possess distinct origins and effector functions, together orchestrating humoral memory responses.

Calcium signals in immune cells regulate a variety of physiological responses such as cell activation, differentiation, gene transcription, and effector functions. Surface receptor stimulation induces an increase in the concentration of cytosolic calcium ions (Ca2+), which are derived mainly from two sources, intracellular endoplasmic reticulum (ER) Ca2+ stores and the extracellular space. The major cascade for Ca2+ entry in immune cells is through store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) channels. Activation of SOCE is triggered by depletion of intracellular ER Ca2+ stores, but the molecular mechanism was a long-standing issue. With the recent molecular identification of the ER Ca2+ sensor [stromal interacting molecule-1 (STIM1)] and a pore-forming subunit of the CRAC channel (Orai1), our understanding of the SOCE activation pathway has increased dramatically. These advances have now made it possible to shed some light on important questions: what is the physiological significance of SOCE, and what is its molecular basis? This review focuses on the recent progress in the field and the exciting opportunities for understanding how SOCE influences diverse immune functions.

In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B-cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. Here, based upon the available genetic and biochemical data of the BCR signal components, we discuss several mechanisms by which BCR signals are propagated and modified, with specific emphasis on the phospholipase C (PLC)-gamma2-calcium pathway Gene-targeting experiments in DT40 chicken B cells highlighted the importance of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma2 activation remained unclear, but new data suggest that an adapter molecule, B-cell linker protein (alternatively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma2 SH2 domains, thus bringing Btk into close proximity with PLC-gamma2. The activated Btk then phosphorylates PLC-gamma2, leading to its activation. The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essential for triggering a calcium release from the ER and subsequent entry of extracellular calcium. Balancing these activation signals in the PLC-gamma2-calcium pathway are the inhibitory receptors expressed on B cells, FcyRII and paired immunoglobin-like receptor (PIR)-B. Although both FcyRII and PIR-B inhibits the BCR-mediated [Ca2+]i increase, the inhibitory mechanisms of these receptors are distinct. The FcyRII-mediated inhibitory signal is dependent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functions of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and FcgammaRII inhibit calcium signals by utilizing two distinct signaling molecules, thereby contributing to setting threshold levels for activation signals as well as terminating activation responses.