1,720,986 research outputs found
The Memory Function of the B Cell Antigen Receptor
No full textActivated B lymphocytes preserve their antigen experience by differentiating into long-lived pools of antibody-secreting plasma cells or various types of memory B cells (MBCs). The former population constantly produces serum immunoglobulins with sufficient specificity and affinity to thwart infections with recurrent pathogens. By contrast, memory B cell populations retain their antigen receptors on the cell surface and hence need pathogen-induced differentiation steps before they can actively contribute to host defense. The terminal differentiation of MBCs into antibody-secreting plasma cells is hallmarked by the absence of the lag phase characteristic for primary antibody responses. Moreover, secondary antibody responses are predominantly driven by MBCs that bear an antigen receptor of the IgG class on their surface although IgM-positive memory populations exist as well. These fundamental principles of B cell memory were enigmatic for decades. Only recently, we have begun to understand the underlying mechanisms. This review summarizes our current understanding of how different subpopulations of MBCs are generated during primary immune responses and how their functional heterogeneity on antigen recall is controlled by different signaling capabilities of B cell antigen receptor (BCR) isotypes and by the nature of the antigen
The signaling tool box for tyrosine-based costimulation of lymphocytes
No full textTriggering lymphocyte effector functions is controlled by a diverse array of immune cell coreceptors that dampen or potentiate the primary activation signal from antigen receptors. Attenuation of lymphocyte activation has been shown to be accomplished by immunoreceptor tyrosine-based inhibition motifs that upon phosphorylation recruit protein or lipid phosphatases. By contrast, a general concept of signal amplification and/or diversification is still out. However, the recent discovery of antigen receptor-intrinsic costimulation by membrane-bound immunoglobulins in class-switched memory B cells identified a consensus phosphorylation motif that can boost antigen-induced signal chains and is also employed by costimulatory receptors on T and Natural Killer cells to provide secondary signals for cellular activation. Here we define a common basis of tyrosine-based lymphocyte costimulation comprising immunoglobulin tail tyrosine (ITT)-like phosphorylation motifs and their proximal effectors, growth factor receptor-bound protein (Grb) 2 and phosphatidylinositol-3 kinase (PI3K) enzymes of class IA
Conformational Plasticity and Navigation of Signaling Proteins in Antigen-Activated B Lymphocytes
No full textOver the past two decades our view of the B cell antigen receptor (BCR) has fundamentally changed. Being initially regarded as a mute antibody orphan of the B cell surface, the BCR turned out to be a complex multimolecular machine monitoring almost all stages of B cell development, selection, and activation through a plethora of ubiquitously and cell-type-specific effector proteins. A comprehensive understanding of the many BCR signaling facets is stilt out but a few common biochemical principles outlined in this review operate at the level of receptor activation and orchestrate specific wiring of intracellular transducer cascades. First, initiation and processing of antigen-induced signal transduction relies on transient conformational changes in the signaling proteins to trigger their physical interaction with downstream elements. Second, this dynamic assembly of signalosomes occurs at distinct subcellular locations, most prominently the plasma membrane, which requires dynamic relocalization of one or more of the engaged molecules. For both, precise complex formation and efficient subcellular targeting, B cell signaling components are equipped with a variety of protein interaction domains. Here we provide an overview on how these simple rules are applied by a limited number of transmembrane and cytosolic proteins to convert BCR ligation into Ca(2+) mobilization and Ras activation in an adjustable manner
Vav family proteins constitute disparate branching points for distinct BCR signaling pathways
No full textsignaling in antigen receptor-activated B lymphocytes
No full textB cells respond to antigen stimulation with mobilization of the Ca2+ second messenger in two phases operated by two distinct sets of effector proteins. First, an antigen receptor-specific Ca2+ initiation complex is assembled, activated, and targeted to the plasma membrane to trigger the transient release of Ca2+ from intracellular stores of the endoplasmic reticulum. Second, more ubiquitously expressed Ca2+ channels of the plasma membrane are opened to allow for sustained Ca2+ influx from the extracellular medium. Depending on the developmental stage of the B cell, the kinetics and profile of the two phases are adjusted at multiple levels of positive and negative regulation. A molecular basis for the Ca2+ signaling plasticity is provided by cytosolic and transmembrane adapter proteins. They act as signal organizers, which control enzyme/substrate interactions by directing the different signaling modules into specific subcellular compartments. These arrangements orchestrate a graduated activation of Ca2+-sensitive downstream pathways, which ultimately determine appropriate cellular responses, namely elimination of autoreactive B cells or proliferation and differentiation of immunocompetent B cells into antibody-secreting plasma cells
The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression
No full textAbstract Immunoglobulin E (IgE) antibodies are key mediators of allergic reactions. Due to their potentially harmful anaphylactic properties, their production is tightly regulated. The membrane‐bound isoform of IgE (mIgE), which is an integral component of the B cell antigen receptor, has been shown to be critical for the regulation of IgE responses in mice. In primate species including humans, mIgE can be expressed in two isoforms that are produced by alternative splicing of the primary ε Ig heavy chain transcript, and differ in the absence or presence of an extracellular membrane‐proximal domain (EMPD) consisting of 52 amino acids. However, the function of the EMPD remains unclear. Here, we demonstrate that the EMPD restricts surface expression of mIgE‐containing BCRs in human and murine B cells. The EMPD does not interfere with BCR assembly but acts as an autonomous endoplasmic reticulum retention domain. Limited surface expression of EMPD‐containing mIgE‐BCRs caused impaired activation of intracellular signaling cascades and hence represents a regulatory mechanism that may control the production of potentially anaphylactic IgE antibodies in primate species
The Non-Ig Parts of the VpreB and lambda 5 Proteins of the Surrogate Light Chain Play Opposite Roles in the Surface Representation of the Precursor B Cell Receptor
No full textThe VpreB and lambda 5 proteins, together with Igm-H chains, form precursor BCRs (preBCRs). We established lambda 5(-/-)/VpreB1(-/-)/ VpreB2(-/-) Abelson virus-transformed cell lines and reconstituted these cells with lambda 5 and VpreB in wild-type form or with a deleted non-Ig part. Whenever preBCRs had the non-Ig part of lambda 5 deleted, surface deposition was increased, whereas deletion of VpreB non-Ig part decreased it. The levels of phosphorylation of Syk, SLP65, or PLC-gamma 2, and of Ca2+ mobilization from intracellular stores, stimulated by mu H chain crosslinking Ab were dependent on the levels of surface-bound preBCRs. It appears that VpreB probes the fitness of newly generated VH domains of IgH chains for later pairing with IgL chains, and its non-Ig part fixes the preBCRs on the surface. By contrast, the non-Ig part of lambda 5 crosslinks preBCRs for downregulation and stimulation. The Journal of Immunology, 2012, 188: 6010-6017
Immunoglobulin divalence promotes B-cell antigen receptor cluster scale-dependent functions
No full textAbstract Antibodies, also known as immunoglobulins, share an evolutionarily conserved dimeric core structure with two antigen binding sites. However, recognition of foreign molecules can be achieved by monovalent binding domains, as evidenced by the T-cell antigen receptor and various innate immune receptors. Thus, the reason for the strict evolutionary conservation of immunoglobulin divalence remains unclear. In addition to being soluble immune effector molecules, each immunoglobulin is also expressed as a membrane-bound isoform in the context of the B-cell antigen receptor (BCR). Here, we generated monovalent BCRs and found that their signaling and antigen internalization capabilities were strongly impaired. By using advanced superresolution imaging of BCRs following stimulation with antigens of distinct valences, we showed that the receptor cluster scale in the plasma membrane determines the magnitude of intracellular signaling. The incorporation of additional ITAMs into single BCRs did not increase receptor sensitivity but caused cellular desensitization. Our results demonstrate that the BCR-controlled signaling machinery senses the clustering status of the BCR and that subtle changes in cluster sizes are translated into cellular responses. These findings improve our knowledge of adaptive immune receptor function and will aid in the design of synthetic chimeric antigen receptors
- …
