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      Igβ tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization

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          Abstract

          Immunoglobulin (Ig)α and Igβ initiate B cell receptor (BCR) signaling through immune receptor tyrosine activation motifs (ITAMs) that are targets of SH2 domain–containing kinases. To examine the function of Igβ ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (Igβ AA). Mutant mice showed normal development of all B cell subtypes with the exception of B1 cells that were reduced by fivefold. However, primary B cells purified from Igβ AA mice showed significantly decreased steady-state and ligand-mediated BCR internalization and higher levels of cell surface IgM and IgD. BCR cross-linking resulted in decreased Src and Syk activation but paradoxically enhanced and prolonged BCR signaling, as measured by cellular tyrosine phosphorylation, Ca ++ flux, AKT, and ERK activation. In addition, B cells with the ITAM mutant receptor showed an enhanced response to a T-independent antigen. Thus, Igβ ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.

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          Most cited references 69

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          Clonal selection and learning in the antibody system.

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          Each antibody-producing B cell makes antibodies of unique specificity, reflecting a series of ordered gene rearrangements which must be successfully performed if the cell is to survive. A second selection process occurs during immune responses in which a new antibody repertoire is generated through somatic hypermutation. Here only mutants binding antigen with high affinity survive to become memory cells. Cells expressing autoreactive receptors are counter-selected at both stages. This stringent positive and negative selection allows the generation and diversification of cells while rigorously controlling their specificity.
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            Immune inhibitory receptors.

            With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                10 July 2006
                : 203
                : 7
                : 1785-1794
                Affiliations
                [1 ]Laboratory of Molecular Immunology and [2 ]Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
                [3 ]Department of Pediatrics, Division of Neonatology, New York University Medical School, New York, NY 10016
                Author notes

                CORRESPONDENCE Anna Gazumyan: gazumya@ 123456mail.rockefeller.edu

                Article
                20060221
                10.1084/jem.20060221
                2118343
                16818674
                Copyright © 2006, The Rockefeller University Press
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