The Journal of Experimental Medicine
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Published online 21 May 2001.
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© The Rockefeller University Press, 0022-1007/2001/5/1169/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 10, May 21, 2001 1169-1178

Original Article

Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the {lambda} Light Chain Locus in Precursor B Cells in the Mouse

Gemma M. Dingjana, Sabine Middendorpa, Katarina Dahlenborga, Alex Maasb, Frank Grosveldb, and Rudolf W. Hendriksa

a Department of Immunology, Faculty of Medicine, Erasmus University Rotterdam, 3000 DR Rotterdam, Netherlands
b Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University Rotterdam, 3000 DR Rotterdam, Netherlands
Department of Immunology, Faculty of Medicine, Rm. Ee851, Erasmus University Rotterdam, Dr. Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, Netherlands.3110-408-94563110-408-7171

hendriks{at}immu.fgg.eur.nl

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase involved in precursor B (pre-B) cell receptor signaling. Here we demonstrate that Btk-deficient mice have an ~50% reduction in the frequency of immunoglobulin (Ig) {lambda} light chain expression, already at the immature B cell stage in the bone marrow. Conversely, transgenic mice expressing the activated mutant BtkE41K showed increased {lambda} usage. As the {kappa}/{lambda} ratio is dependent on (a) the level and kinetics of {kappa} and {lambda} locus activation, (b) the life span of pre-B cells, and (c) the extent of receptor editing, we analyzed the role of Btk in these processes. Enforced expression of the Bcl-2 apoptosis inhibitor did not alter the Btk dependence of {lambda} usage. Crossing 3-83µ{delta} autoantibody transgenic mice into Btk-deficient mice showed that Btk is not essential for receptor editing. Also, Btk-deficient surface Ig+ B cells that were generated in vitro in interleukin 7-driven bone marrow cultures manifested reduced {lambda} usage. An intrinsic defect in {lambda} locus recombination was further supported by the finding in Btk-deficient mice of reduced {lambda} usage in the fraction of pre-B cells that express light chains in their cytoplasm. These results implicate Btk in the regulation of the activation of the {lambda} locus for V(D)J recombination in pre-B cells.

Key Words: Btk • B lymphocytes • Ig L chain • receptor editing • V(D)J rearrangements

Abbreviations used in this paper: BCR, B cell receptor; Btk, Bruton's tyrosine kinase; PH, pleckstrin homology; WT, wild-type; Xid, X-linked immunodeficiency; XLA, X-linked agammaglobulinemia.

© 2001 The Rockefeller University Press


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