PMID:14734712

Citation	Middendorp, S and Hendriks, RW (2004) Cellular maturation defects in Bruton's tyrosine kinase-deficient immature B cells are amplified by premature B cell receptor expression and reduced by receptor editing. J. Immunol. 172:1371-9
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.
Links	PubMed
Keywords	Animals; B-Lymphocyte Subsets/enzymology; B-Lymphocyte Subsets/immunology; B-Lymphocyte Subsets/metabolism; B-Lymphocyte Subsets/pathology; Cell Differentiation/genetics; Cell Differentiation/immunology; Cell Movement/genetics; Cell Movement/immunology; Cells, Cultured; Clonal Deletion/genetics; Down-Regulation/genetics; Down-Regulation/immunology; Gene Rearrangement, B-Lymphocyte/genetics; Gene Rearrangement, B-Lymphocyte/immunology; Hematopoietic Stem Cells/enzymology; Hematopoietic Stem Cells/immunology; Hematopoietic Stem Cells/pathology; Immunoglobulin delta-Chains/genetics; Immunoglobulin kappa-Chains/biosynthesis; Immunoglobulin lambda-Chains/biosynthesis; Immunoglobulin mu-Chains/genetics; Lymphopenia/enzymology; Lymphopenia/genetics; Lymphopenia/immunology; Lymphopenia/pathology; Membrane Glycoproteins/biosynthesis; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pre-B Cell Receptors; Protein-Tyrosine Kinases/biosynthesis; Protein-Tyrosine Kinases/deficiency; Protein-Tyrosine Kinases/genetics; Proto-Oncogene Proteins c-bcl-2/biosynthesis; Proto-Oncogene Proteins c-bcl-2/genetics; Receptors, Antigen, B-Cell/biosynthesis; Receptors, Antigen, B-Cell/genetics; Spleen/immunology; Spleen/pathology; Up-Regulation/genetics; Up-Regulation/immunology
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