Abstract
In the mouse, Bruton's tyrosine kinase (Btk) is essential for efficient developmental progression of CD43(+)CD2(-) large cycling into CD43(-)CD2(+) small resting pre-B cells in the bone marrow and of IgM(high) transitional type 2 B cells into IgM(low) mature B cells in the spleen. In this study, we show that the impaired induction of cell surface changes in Btk-deficient pre-B cells was still noticeable in kappa(+) immature B cells, but was largely corrected in lambda(+) immature B cells. As lambda gene rearrangements are programmed to follow kappa rearrangements and lambda expression is associated with receptor editing, we hypothesized that the transit time through the pre-B cell compartment or receptor editing may affect the extent of the cellular maturation defects in Btk-deficient B cells. To address this issue, we used 3-83 mu delta transgenic mice, which prematurely express a complete B cell receptor and therefore manifest accelerated B cell development. In Btk-deficient 3-83 mu delta mice, the IgM(+) B cells in the bone marrow exhibited a very immature phenotype (pre-BCR(+)CD43(+)CD2(-)) and were arrested at the transitional type 1 B cell stage upon arrival in the spleen. However, these cellular maturation defects were largely restored when Btk-deficient 3-83 mu delta B cells were on a centrally deleting background and therefore targeted for receptor editing. Providing an extended time window for developing B cells by enforced expression of the antiapoptotic gene Bcl-2 did not alter the Btk dependence of their cellular maturation. We conclude that premature B cell receptor expression amplifies the cellular maturation defects in Btk-deficient B cells, while extensive receptor editing reduces these defects.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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B-Lymphocyte Subsets / enzymology
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B-Lymphocyte Subsets / immunology
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B-Lymphocyte Subsets / metabolism
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B-Lymphocyte Subsets / pathology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Movement / genetics
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Cell Movement / immunology
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Cells, Cultured
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Clonal Deletion / genetics
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Gene Rearrangement, B-Lymphocyte / genetics
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Gene Rearrangement, B-Lymphocyte / immunology*
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Hematopoietic Stem Cells / enzymology*
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / pathology
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Immunoglobulin delta-Chains / genetics
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Immunoglobulin kappa-Chains / biosynthesis
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Immunoglobulin lambda-Chains / biosynthesis
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Immunoglobulin mu-Chains / genetics
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Lymphopenia / enzymology
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Lymphopenia / genetics
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Lymphopenia / immunology
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Lymphopenia / pathology
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Pre-B Cell Receptors
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / deficiency*
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Protein-Tyrosine Kinases / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Receptors, Antigen, B-Cell / biosynthesis*
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Receptors, Antigen, B-Cell / genetics
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Spleen / immunology
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Spleen / pathology
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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Immunoglobulin delta-Chains
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Immunoglobulin kappa-Chains
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Immunoglobulin lambda-Chains
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Immunoglobulin mu-Chains
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Membrane Glycoproteins
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Pre-B Cell Receptors
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, B-Cell
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse