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

Correspondence to: Rudolf W. Hendriks, Department of Immunology, Faculty of Medicine, Rm. Ee851, Erasmus University Rotterdam, Dr. Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, Netherlands. Tel:3110-408-7171 Fax:3110-408-9456 E-mail: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


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