title: 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.
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.
authors.affiliation: Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Middendorp
authors.forename: Rudolf W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017637:Clonal Deletion / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007138:Immunoglobulin delta-Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis; D007146:Immunoglobulin lambda-Chains / Q000096:biosynthesis; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054420:Pre-B Cell Receptors; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis* / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D007138:Immunoglobulin delta-Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D007148:Immunoglobulin mu-Chains; D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse