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Ig Heavy Chain Promotes Mature B Cell Survival in the Absence of Light Chain¹

Pedro Geraldes^*, Michelle Rebrovich^*, Kai Herrmann^¶, Jamie Wong^||, Hans-Martin Jäck^¶, Matthias Wabl^|| and Marilia Cascalho^2,*,,

^* Transplantation Biology Program and Department of Immunology, Deparment of Surgery, and Department of Pediatrics, Mayo Clinic College of Medicine, Rochester, MN 55905; ^¶ Division of Molecular Immunology, Nikolaus-Fiebiger Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; and ^|| Department of Microbiology and Immunology, University of California, San Francisco 94143

Survival of mature B cells is thought to depend on the BCR signaling (BCR) because ablation of either H chain (HC) expression or BCR signaling causes B cells to rapidly disappear. Whether a complete BCR is required for survival of mature B cells is not known. To address this question, we generated a mouse in which we can repress the expression of a transgenic Ig L chain (IgL) by doxycycline (IgL-repressible mouse). Repression of IgL abrogated expression. Surprisingly, however, IgL-negative B cells survived longer than 14 wk, expressed signal-competent HC on the cell’s surface, and active unfolded protein response factors. Like postgerminal center B cells, IgL-negative B cells were small lymphocytes, not dividing and expressed Bcl-6. Our results indicate that expression of unpaired HC, as it may occur as a consequence of Ag ligation, somatic hypermutation, or receptor editing, facilitates the survival of cells either by inducing receptor signaling or by inducing unfolded protein response and/or the expression of survival genes such as Bcl-6.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI48602, AI61100, AI53733, AI41570, and HL79067. This work was also supported by the Interdisciplinary Center for Clinical Research and the Deutsche Forschungsgemeinschaft (SFB 466 and FOR 832 research grant JA 96814) to H.-M.J. and the training grant GRK592 from the Deutsche Forschungsgemeinschaft to K.H.

² Address correspondence and reprint requests to Dr. Marilia Cascalho, Mayo Clinic, 200 First Street SW, Medical Sciences 2-75, Rochester, MN 55905. E-mail address: cascalho.marilia{at}mayo.edu

³ Abbreviations used in this paper: HC, H chain; LC, L chain; SL, surrogate L; BiP, H chain-binding protein; ER, endoplasmic reticulum; tTA, tetracycline transactivator; MMTV-tTA, mouse mammary tumor virus tTA; Pmin, minimal promoter; TetO, transactivator-responsive promoter; T_m, melting temperature; RT, room temperature; DOX, doxycycline; aid/AID, activation-induced cytidine deaminase; UPR, unfolded protein response; Chop/chop, C/EBP homologous protein.