The Journal of Experimental Medicine
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Published online 1 June 2004 doi:10.1084/jem.20031523
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1523-1532
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Surface µ Heavy Chain Signals Down-Regulation of the V(D)J-Recombinase Machinery in the Absence of Surrogate Light Chain Components

Gunther R. Galler1, Cornelia Mundt2, Mathew Parker2, Roberta Pelanda3, Inga-Lill Mårtensson2, and Thomas H. Winkler1

1 Hematopoiesis Unit, Nikolaus-Fiebiger-Center, Friedrich-Alexander University, 91054 Erlangen, Germany
2 Developmental Immunology, The Babraham Institute, Babraham, CB2 4AT Cambridge, England, UK
3 Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, CO 80206

Address correspondence to Thomas H. Winkler, Hematopoiesis Unit, Nikolaus-Fiebiger-Center, Glueckstrasse 6, 91054 Erlangen, Germany. Phone: 49-9131-8529136; Fax: 49-9131-8529106; email: twinkler{at}molmed.uni-erlangen.de

Early B cell development is characterized by stepwise, ordered rearrangement of the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the two alleles of these genes is used to produce a receptor, a phenomenon referred to as allelic exclusion. It has been suggested that pre–B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele. Using a mouse model, we show that expression of an inducible µHC transgene in Rag2–/– pro–B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts. Similar effects were also observed in the absence of surrogate LC (SLC) components, but not in the absence of the signaling subunit Ig-{alpha}. Furthermore, in wild-type mice and in mice lacking either {lambda}5, VpreB1/2, or the entire SLC, the TdT protein is down-regulated in µHC+LC– pre–B cells. Surprisingly, µHC without LC is expressed on the surface of pro–/pre–B cells from {lambda}5–/–, VpreB1–/–VpreB2–/–, and SLC–/– mice. Thus, SLC or LC is not required for µHC cell surface expression and signaling in these cells. Therefore, these findings offer an explanation for the occurrence of HC allelic exclusion in mice lacking SLC components.

Key Words: B cell development • allelic exclusion • Rag • TdT • pre-BCR

Abbreviations used in this paper: EAS, enzyme amplification staining; FISH, fluorescent in situ hybridization; GFP, green fluorescent protein; HC, heavy chain; LC, light chain; pre-BCR, pre–B cell receptor; SLC, surrogate LC; TdT, terminal deoxynucleotidyl transferase.


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