Abstract
Motheaten viable (mev) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTP1C in B cell selection and function was analyzed by breeding immunoglobulin transgenes specific for a defined antigen, hen egg lysozyme, into mev mice. Antigen triggered a greater and more rapid elevation of intracellular calcium in PTP1C-deficient B cells, indicating that this phosphatase negatively regulates immunoglobulin signaling. Elimination of self-reactive B cells carrying this signal-enhancing mutation was triggered during their development by binding a lower valency form of self-antigen than is normally required. These findings establish that activation of distinct repertoire-censoring mechanisms depends on quantitative differences in antigen receptor signaling, whose thresholds are determined by negative regulation through PTP1C.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibody Diversity / physiology*
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Antigens / immunology
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B-Lymphocyte Subsets*
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Bone Marrow / pathology
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Calcium / physiology
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Immunoglobulin D / immunology*
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Immunoglobulin M / immunology*
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Immunologic Deficiency Syndromes / enzymology
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Immunologic Deficiency Syndromes / genetics
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Immunologic Deficiency Syndromes / immunology*
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Intracellular Signaling Peptides and Proteins
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Lymphocyte Activation / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Mice, Transgenic
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Muramidase / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / deficiency
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology*
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Radiation Chimera / immunology
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Receptors, Antigen, B-Cell / physiology*
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Self Tolerance
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Signal Transduction / physiology
Substances
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Antigens
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Immunoglobulin D
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Immunoglobulin M
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Intracellular Signaling Peptides and Proteins
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Receptors, Antigen, B-Cell
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse
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Muramidase
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Calcium