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
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.
|Keywords||Animals, B-Lymphocyte Subsets/enzymology/immunology/metabolism/*pathology, Cell Differentiation/genetics/immunology, Cell Movement/genetics/immunology, Cells, Cultured, Clonal Deletion/genetics, Comparative Study, Down-Regulation/genetics/*immunology, Gene Rearrangement, B-Lymphocyte/genetics/*immunology, Hematopoietic Stem Cells/*enzymology/immunology/pathology, Immunoglobulin delta-Chains/genetics, Immunoglobulin kappa-Chains/biosynthesis, Immunoglobulin lambda-Chains/biosynthesis, Immunoglobulin mu-Chains/genetics, Lymphopenia/enzymology/genetics/immunology/pathology, Membrane Glycoproteins/*biosynthesis/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Protein-Tyrosine Kinase/biosynthesis/*deficiency/genetics, Proto-Oncogene Proteins c-bcl-2/biosynthesis/genetics, Receptors, Antigen, B-Cell/*biosynthesis/genetics, Research Support, Non-U.S. Gov't, Spleen/immunology/pathology, Up-Regulation/genetics/*immunology|
Middendorp, S., & Hendriks, R.W.. (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. Journal of Immunology, 172(3), 1371–1379. Retrieved from http://hdl.handle.net/1765/10300