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Antigen Receptor Signaling

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Cosima T. Baldari – One of the best experts on this subject based on the ideXlab platform.

  • The Shc family protein adaptor, Rai, negatively regulates T cell Antigen Receptor Signaling by inhibiting ZAP-70 recruitment and activation.
    PLoS ONE, 2011
    Co-Authors: Micol Ferro, Francesca Finetti, Maria Teresa Savino, Barbara Ortensi, Luca Genovese, Giulia Masi, Cristina Ulivieri, Daniela Benati, Giuliana Pelicci, Cosima T. Baldari


    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.

  • Positive and negative regulation of Antigen Receptor Signaling by the Shc family of protein adapters
    Immunological Reviews, 2009
    Co-Authors: Francesca Finetti, Maria Teresa Savino, Cosima T. Baldari


    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.

  • rai acts as a negative regulator of autoimmunity by inhibiting Antigen Receptor Signaling and lymphocyte activation
    Journal of Immunology, 2009
    Co-Authors: Maria Teresa Savino, Micol Ferro, Barbara Ortensi, Cristina Ulivieri, Giuliana Pelicci, Daniela Fanigliulo, Eugenio Paccagnini, Stefano Lazzi, Daniela Osti, Cosima T. Baldari


    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.

Arthur Weiss – One of the best experts on this subject based on the ideXlab platform.

  • endogenous nur77 is a specific indicator of Antigen Receptor Signaling in human t and b cells
    Journal of Immunology, 2017
    Co-Authors: Judith F Ashouri, Arthur Weiss


    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.

  • 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, 2014
    Co-Authors: Byron B Auyeung, Julie Zikherman, James L Mueller, Judith F Ashouri, Mehrdad Matloubian, Debra A Cheng, Yiling Chen, Kevan M Shokat, Arthur Weiss


    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.

  • Antigen Receptor Signaling in the rheumatic diseases
    Arthritis Research & Therapy, 2009
    Co-Authors: Julie Zikherman, Arthur Weiss


    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.

John C. Cambier – One of the best experts on this subject based on the ideXlab platform.

  • B lymphocyte Antigen Receptor Signaling: initiation, amplification, and regulation.
    F1000Prime Reports, 2013
    Co-Authors: Thomas A. Packard, John C. Cambier


    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.

  • B cell Antigen Receptor Signaling 101.
    Molecular Immunology, 2004
    Co-Authors: Joseph M. Dal Porto, Stephen B. Gauld, Kevin T. Merrell, David M. Mills, Aimee E. Pugh-bernard, John C. Cambier


    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.

  • B cell Antigen Receptor Signaling: roles in cell development and disease.
    Science, 2002
    Co-Authors: Stephen B. Gauld, Joseph M. Dal Porto, John C. Cambier


    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.