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Cosima T. Baldari - One of the best experts on this subject based on the ideXlab platform.
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The Shc family protein adaptor, Rai, negatively regulates T cell Antigen Receptor Signaling by inhibiting ZAP-70 recruitment and activation.
PLoS ONE, 2011Co-Authors: Micol Ferro, Francesca Finetti, Maria Teresa Savino, Barbara Ortensi, Luca Genovese, Giulia Masi, Cristina Ulivieri, Daniela Benati, Giuliana Pelicci, Cosima T. BaldariAbstract:Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic Receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates Antigen Receptor Signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR Signaling. We show that Rai interferes with the TCR Signaling cascade one of the earliest steps –recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream Signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological Signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key Signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR Signaling cascade.
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Positive and negative regulation of Antigen Receptor Signaling by the Shc family of protein adapters
Immunological Reviews, 2009Co-Authors: Francesca Finetti, Maria Teresa Savino, Cosima T. BaldariAbstract:The Shc adapter family includes four members that are expressed as multiple isoforms and participate in Signaling by a variety of cell-surface Receptors. The biological relevance of Shc proteins as well as their variegated function, which relies on their highly conserved modular structure, is underscored by the distinct and dramatic phenotypic alterations resulting from deletion of individual Shc isoforms both in the mouse and in two model organisms, Drosophila melanogaster and Caenorhabditis elegans. The p52 isoform of ShcA couples Antigen and cytokine Receptors to Ras activation in both lymphoid and myeloid cells. However, the recognition of the spectrum of activities of p52ShcA in the immune system has been steadily expanding in recent years to other fundamental processes both at the cell and organism levels. Two other Shc family members, p66ShcA and p52ShcC/Rai, have been identified recently in T and B lymphocytes, where they antagonize survival and attenuate Antigen Receptor Signaling. These developments reveal an unexpected and complex interplay of multiple Shc proteins in lymphocytes.
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rai acts as a negative regulator of autoimmunity by inhibiting Antigen Receptor Signaling and lymphocyte activation
Journal of Immunology, 2009Co-Authors: Maria Teresa Savino, Micol Ferro, Barbara Ortensi, Cristina Ulivieri, Giuliana Pelicci, Daniela Fanigliulo, Eugenio Paccagnini, Stefano Lazzi, Daniela Osti, Cosima T. BaldariAbstract:Rai (ShcC) belongs to the family of Shc adaptor proteins and is expressed in neuronal cells, where it acts as a survival factor activating the PI3K/Akt survival pathway. In vivo, Rai protects the brain from ischemic damage. In this study, we show that Rai is expressed in T and B lymphocytes. Based on the finding that Rai−/− mice consistently develop splenomegaly, the role of Rai in lymphocyte homeostasis and proliferation was addressed. Surprisingly, as opposed to neurons, Rai was found to impair lymphocyte survival. Furthermore, Rai deficiency results in a reduction in the frequency of peripheral T cells with a concomitant increase in the frequency of B cells. Rai−/− lymphocytes display enhanced proliferative responses to Ag Receptor engagement in vitro, which correlates with enhanced Signaling by the TCR and BCR, and more robust responses to allergen sensitization in vivo. A high proportion of Rai−/− mice develop a lupus-like autoimmune syndrome characterized by splenomegaly, spontaneous peripheral T and B cell activation, autoantibody production, and deposition of immune complexes in the kidney glomeruli, resulting in autoimmune glomerulonephritis. The data identify Rai as a negative regulator of lymphocyte survival and activation and show that loss of this protein results in breaking of immunological tolerance and development of systemic autoimmunity.
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Antigen Receptor Signaling: the Tuscan connection.
Nature Immunology, 2007Co-Authors: Cosima T. Baldari, Gary A. KoretzkyAbstract:At the first meeting of the new three-part EMBO Conference series on “Signaling in the immune system,” immunologists presented key findings and highlighted new questions and emerging trends.
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anthrax toxins suppress t lymphocyte activation by disrupting Antigen Receptor Signaling
Journal of Experimental Medicine, 2005Co-Authors: Silvia Rossi Paccani, Fiorella Tonello, Raffaella Ghittoni, Mariarita Natale, Lucia Muraro, Mario Milco Delios, Weijen Tang, Cesare Montecucco, Cosima T. BaldariAbstract:Anthrax is an infection caused by pathogenic strains of Bacillus anthracis, which secretes a three-component toxic complex consisting of protective Antigen (PA), edema factor (EF), and lethal factor (LF). PA forms binary complexes with either LF or EF and mediates their entry into host cells. Although the initial phases of bacterial growth occur in the lymph node, the host fails to mount an effective immune response. Here, we show that LT and ET are potent suppressors of human T cell activation and proliferation triggered through the Antigen Receptor. Both LT and ET inhibit the mitogen-activated protein and stress kinase pathways, and both toxins inhibit activation of NFAT and AP-1, two transcription factors essential for cytokine gene expression. These data identify a novel strategy of immune evasion by B. anthracis, based on both effector subunits of the toxic complex, and targeted to a key cellular component of adaptive immunity.
Arthur Weiss - One of the best experts on this subject based on the ideXlab platform.
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endogenous nur77 is a specific indicator of Antigen Receptor Signaling in human t and b cells
Journal of Immunology, 2017Co-Authors: Judith F Ashouri, Arthur WeissAbstract:Distinguishing true Ag-stimulated lymphocytes from bystanders activated by the inflammatory milieu has been difficult. Nur77 is an immediate early gene whose expression is rapidly upregulated by TCR Signaling in murine T cells and human thymocytes. Nur77-GFP transgenes serve as specific TCR and BCR Signaling reporters in murine transgenic models. In this study, we demonstrate that endogenous Nur77 protein expression can serve as a reporter of TCR and BCR specific Signaling in human PBMCs. Nur77 protein amounts were assessed by immunofluorescence and flow cytometry in T and B cells isolated from human PBMCs obtained from healthy donors that had been stimulated by their respective Ag Receptors. We demonstrate that endogenous Nur77 is a more specific reporter of Ag-specific Signaling events than the commonly used CD69 activation marker in both human T and B cells. This is reflective of the disparity in Signaling pathways that regulate the expression of Nur77 and CD69. Assessing endogenous Nur77 protein expression has great potential to identify Ag-activated lymphocytes in human disease.
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a sharp t cell Antigen Receptor Signaling threshold for t cell proliferation
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Byron B Auyeung, Julie Zikherman, James L Mueller, Judith F Ashouri, Mehrdad Matloubian, Debra A Cheng, Yiling Chen, Kevan M Shokat, Arthur WeissAbstract:T-cell Antigen Receptor (TCR) Signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR Signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR Signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77–eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR Signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR Signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR Signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.
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Antigen Receptor Signaling in the rheumatic diseases
Arthritis Research & Therapy, 2009Co-Authors: Julie Zikherman, Arthur WeissAbstract:Antigen Receptor Signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell Signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell Receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythema-tosus in mice and humans. Impaired and enhanced T-cell Receptor Signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.
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Review Antigen Receptor Signaling in the rheumatic diseases
2009Co-Authors: Julie Zikherman, Arthur WeissAbstract:Antigen Receptor Signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell Signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell Receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythematosus in mice and humans. Impaired and enhanced T-cell Receptor Signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.
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Lymphocytes with a complex: adapter proteins in Antigen Receptor Signaling.
Immunology Today, 2000Co-Authors: Michael G. Tomlinson, Joseph Lin, Arthur WeissAbstract:Adapters can be defined as proteins that mediate intermolecular interactions within a signal transduction pathway and that lack both intrinsic enzymatic and transcriptional activity. Their essential role in lymphocyte Signaling was revealed by recent analyses of mice and cell lines deficient in LAT, SLP-76 and BLNK. These and other adapters nucleate Signaling complexes and facilitate coupling of Antigen Receptor triggering to functional responses in lymphocytes.
John C. Cambier - One of the best experts on this subject based on the ideXlab platform.
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B lymphocyte Antigen Receptor Signaling: initiation, amplification, and regulation.
F1000Prime Reports, 2013Co-Authors: Thomas A. Packard, John C. CambierAbstract:B lymphocytes and their differentiated daughters are charged with responding to the myriad pathogens in our environment and production of protective antibodies. A sample of the protective antibody produced by each clone is utilized as a component of the cell’s Antigen Receptor (BCR). Transmembrane signals generated upon Antigen binding to this Receptor provide the primary directive for the cell’s subsequent response. In this report, we discuss recent progress and current controversy regarding B cell Receptor signal initiation, transduction and regulation.
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B cell Antigen Receptor Signaling 101.
Molecular Immunology, 2004Co-Authors: Joseph M. Dal Porto, Stephen B. Gauld, Kevin T. Merrell, David M. Mills, Aimee E. Pugh-bernard, John C. CambierAbstract:Abstract All cells continually survey their environment and make decisions based on cues encountered. This requires specific Receptors that detect such cues, then transduce signals that initiate the appropriate responses. B lymphocytes provide an archetypal model for such ‘adaptive’ cellular responses, where signals transmitted by the B cell Ag-Receptor (BCR) influence not only cellular selection, maturation, and survival, but are imperative in generating the ultimate effector function of B cells, i.e. antibody production. While other extracellular stimuli and their cognate Receptor signals can also influence B cell development, BCR-mediated signals and the way in which they are integrated and regulated are paramount in defining the cell’s physiological fate.
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B cell Antigen Receptor Signaling: roles in cell development and disease.
Science, 2002Co-Authors: Stephen B. Gauld, Joseph M. Dal Porto, John C. CambierAbstract:Signals propagated through the B cell Antigen Receptor (BCR) are vital for the development and survival of B lymphocytes in both the bone marrow and the periphery. These signals not only guide maturation and activation but also affect the removal of potentially self-reactive B lymphocytes. Interestingly, these signals are known to be either ligand-independent ("tonic" signals) or induced by ligand (Antigen) binding to the BCR. We focus on the problems that occur in B cell development due to defects in signals emanating from the BCR. In addition, we present the B Cell Antigen Receptor Pathway, an STKE Connections Map that illustrates the events involved in B cell Signaling.
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Antigen Receptor Signaling : Integration of protein tyrosine kinase functions
Oncogene, 1998Co-Authors: Idan Tamir, John C. CambierAbstract:Antigen Receptors on T and B cells function to transduce signals leading to a variety of biologic responses minimally including Antigen Receptor editing, apoptotic death, developmental progression, cell activation, proliferation and survival. The response to Antigen depends upon Antigen affinity and valence, involvement of coReceptors in Signaling and differentiative stage of the responding cell. The requirement that these Receptors integrate signals that drive an array of responses may explain their evolved structural complexity. Antigen Receptors are composed of multiple subunits compartmentalized to provide Antigen recognition and signal transduction function. In lieu of on-board enzymatic activity these Receptors rely on associated Protein Tyrosine Kinases (PTKs) for their Signaling function. By aggregating the Receptors, and hence their appended PTKs, Antigens induce PTK transphosphorylation, activating them to phosphorylate the Receptor within conserved motifs termed ImmunoReceptor Tyrosine-based Activation Motifs (ITAMs) found in transducer subunits. The tyrosyl phosphorylated ITAMs then interact with Src Homology 2 (SH2) domains within the PTKs leading to their further activation. As Receptor phosphorylation is amplified, other effectors, such as Shc, dock by virtue of SH2 binding, and serve, in-turn, as substrates for these PTKs. This sequence of events not only provides a signal amplification mechanism by combining multiple consecutive steps with positive feedback, but also allows for signal diversification by differential recruitment of effectors that provide access to distinct parallel downstream Signaling pathways. The subject of Antigen Receptor Signaling has been recently reviewed in depth (; ). Here we discuss the biochemical basis of Antigen Receptor signal transduction, using the B cell Receptor (BCR) as a paradigm, with specific emphasis on the involved PTKs. We review several specific mechanisms by which responses through these Receptors are propagated and modified by accessory molecules, and discuss how signal amplification and diversification are achieved.
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Qualitative regulation of B cell Antigen Receptor Signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.
Journal of Experimental Medicine, 1997Co-Authors: Anne Mette Buhl, Christopher M. Pleiman, Robert C. Rickert, John C. CambierAbstract:Genetic ablation of the B cell surface glycoprotein CD19 severely impairs the humoral immune response. This requirement is thought to reflect a critical role of CD19 in signal transduction that occurs upon Antigen C3dg coligation of Antigen Receptors with CD19 containing type 2 complement Receptors (CR2). Here we show that CD19 plays a key accessory role in B cell Antigen Receptor Signaling independent of CR2 coligation and define molecular circuitry by which this function is mediated. While CD19 is not required for Antigen-mediated activation of Receptor proximal tyrosines kinases, it is critical for activation of phosphatidylinositol 3-kinase (PI3-kinase). PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515. Antigen-induced CD19-dependent PI3-kinase activation is required for normal phosphoinositide hydrolysis and Ca2+ mobilization responses. Thus, CD19 functions as a B cell Antigen Receptor accessory molecule that modifies Antigen Receptor Signaling in a qualitative manner.
Susan K Pierce - One of the best experts on this subject based on the ideXlab platform.
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the cd19 cd21 complex functions to prolong b cell Antigen Receptor Signaling from lipid rafts
Immunity, 2001Co-Authors: Anu Cherukuri, Paul C Cheng, Hae Won Sohn, Susan K PierceAbstract:The CD19/CD21 complex functions to significantly enhance B cell Antigen Receptor (BCR) Signaling in response to complement-tagged Antigens. Recent studies showed that following Antigen binding the BCR translocates into plasma membrane lipid rafts that serve as platforms for BCR Signaling. Here, we show that the binding of complement-tagged Antigens stimulates the translocation of both the BCR and the CD19/CD21 complex into lipid rafts, resulting in prolonged residency in and Signaling from the rafts, as compared to BCR cross-linking alone. When coligated to the BCR, the CD19/CD21 complex retards the internalization and degradation of the BCR. The colocalization and stabilization of the BCR and the CD19/CD21 complex in plasma membrane lipid rafts represents a novel mechanism by which a coReceptor enhances BCR Signaling.
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cutting edge b cell Antigen Receptor Signaling occurs outside lipid rafts in immature b cells
Journal of Immunology, 2000Co-Authors: Tim W Sproul, Sunil Malapati, Julie Kim, Susan K PierceAbstract:B cell Ag Receptor (BCR) Signaling changes dramatically during B cell development, resulting in activation in mature B cells and apoptosis, Receptor editing, or anergy in immature B cells. BCR Signaling in mature B cells was shown to be initiated by the translocation of the BCR into cholesterol- and sphingolipid-enriched membrane microdomains that include the Src family kinase Lyn and exclude the phosphatase CD45. Subsequently the BCR is rapidly internalized into the cell. Here we show that the BCR in the immature B cell line, WEHI-231, does not translocate into lipid rafts following cross-linking nor is the BCR rapidly internalized. The immature BCR initiates Signaling from outside lipid rafts as evidenced by the immediate induction of an array of phosphoproteins and subsequent apoptosis. The failure of the BCR in immature B cells to enter lipid rafts may contribute to the dramatic difference in the outcome of Signaling in mature and immature B cells.
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a role for lipid rafts in b cell Antigen Receptor Signaling and Antigen targeting
Journal of Experimental Medicine, 1999Co-Authors: Paul C Cheng, Michelle L Dykstra, Richard N Mitchell, Susan K PierceAbstract:The B cell Antigen Receptor (BCR) serves both to initiate signal transduction cascades and to target Antigen for processing and presentation by MHC class II molecules. How these two BCR functions are coordinated is not known. Recently, sphingolipid- and cholesterol-rich plasma membrane lipid microdomains, termed lipid rafts, have been identified and proposed to function as platforms for both Receptor Signaling and membrane trafficking. Here we show that upon cross-linking, the BCR rapidly translocates into ganglioside GM1-enriched lipid rafts that contain the Src family kinase Lyn and exclude the phosphatase CD45R. Both Igα and Lyn in the lipid rafts become phosphorylated, and subsequently the BCR and a portion of GM1 are targeted to the class II peptide loading compartment. Entry into lipid rafts, however, is not sufficient for targeting to the Antigen processing compartments, as a mutant surface Ig containing a deletion of the cytoplasmic domain is constitutively present in rafts but when cross-linked does not internalize to the Antigen processing compartment. Taken together, these results provide evidence for a role for lipid rafts in the initial steps of BCR Signaling and Antigen targeting.
Michael Reth - One of the best experts on this subject based on the ideXlab platform.
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suboptimal b cell Antigen Receptor Signaling activity in vivo elicits germinal center counterselection mechanisms
European Journal of Immunology, 2015Co-Authors: Sebastian Konigsberger, Michael Reth, Vanessa Weis, Jan Prodohl, Martin Stehling, Elias Hobeika, Friedemann KieferAbstract:Syk and Zap-70 constitute a closely related nonReceptor protein tyrosine kinase family, of which both members are functionally indispensable for conferring their respective Antigen Receptors with enzymatic activity. In this study, we analyze the impact of altering BCR Signaling output on B-cell germinal center (GC) fate selection by constitutive, as well as inducible, monoallelic Syk kinase loss in the presence of a Zap-70 knock-in rescue allele. Cre-mediated Syk deletion in Syk(flox/Zap-70) B cells lowers pErk, but not pAkt-mediated Signaling. Surprisingly, the use of a B-cell-specific constitutive mb1-cre deleter mouse model showed that a small cohort of peripheral Syk(flox/Zap-70);mb1-cre B cells efficiently circumvents deletion, which ultimately favors these Syk-sufficient cells to contribute to the GC reaction. Using a developmentally unbiased Syk(flox/Zap-70);mb1-creER(T2) approach in combination with an inducible tdRFP allele, we further demonstrate that this monoallelic deletion escape is not fully explained by leakiness of Cre expression, but is possibly the result of differential Syk locus accessibility in maturing B cells. Altogether, this underscores the importance of proper Syk kinase function not only during central and peripheral selection processes, but also during GC formation and maintenance.
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amplification of b cell Antigen Receptor Signaling by a syk itam positive feedback loop
Molecular Cell, 2002Co-Authors: Veronique Rolli, Maike Gallwitz, Thomas Wossning, Alexandra Flemming, Wolfgang W A Schamel, Christa Zurn, Michael RethAbstract:We have established a protocol allowing transient and inducible coexpression of many foreign genes in Drosophila S2 Schneider cells. With this powerful approach of reverse genetics, we studied the interaction of the protein tyrosine kinases Syk and Lyn with the B cell Antigen Receptor (BCR). We find that Lyn phosphorylates only the first tyrosine whereas Syk phosphorylates both tyrosines of the BCR immunoReceptor tyrosine-based activation motif (ITAM). Furthermore, we show that Syk is a positive allosteric enzyme, which is strongly activated by the binding to the phosphorylated ITAM tyrosines, thus initiating a positive feedback loop at the Receptor. The BCR-dependent Syk activation and signal amplification is efficiently counterbalanced by protein tyrosine phosphatases, the activity of which is regulated by H(2)O(2) and the redox equilibrium inside the cell.