The Journal of Experimental Medicine
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Published online May 19, 2008
doi:10.1084/jem.20080238
The Journal of Experimental Medicine, Vol. 205, No. 6, 1317-1329
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Hömig-Hölzel et al.
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ARTICLE

 Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-{kappa}B pathway and promotes lymphomagenesis

Cornelia Hömig-Hölzel1, Caroline Hojer1, Julia Rastelli1, Stefano Casola2, Lothar J. Strobl1, Werner Müller3, Leticia Quintanilla-Martinez4, Andreas Gewies5, Jürgen Ruland5, Klaus Rajewsky2, and Ursula Zimber-Strobl1

1 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany
2 Immune Disease Institute, Harvard Medical School, Boston, MA 02115
3 The Department of Experimental Immunology, Helmholtz Center for Infectious Research, D-38124 Braunschweig, Germany
4 Institute of Pathology, Helmholtz Center Munich, German Research Center for Environment and Health, D-85764 Neuherberg, Germany
5 III Med. Department, Technical University of Munich, Klinikum rechts der Isar, D-81675 Munich, Germany

CORRESPONDENCE Ursula Zimber-Strobl: strobl{at}helmholtz-muenchen.de

CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell–dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-{kappa}B pathway and the mitogen-activated protein kinases Jnk and extracellular signal–regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.

Abbreviations used: Erk, extracellular signal–regulated kinase; ES, embryonic stem; GC, germinal center; HE, hematoxylin and eosin; LMP, latent membrane protein; MAPK, mitogen-activated protein kinase; TD, T cell dependent.

C. Hömig-Hölzel and C. Hojer contributed equally to this paper.

S. Casola's present address is IFOM-The Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy.

C. Hömig-Hölzel's present address is Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, Netherlands.

J. Rastelli's present address is Whitehead Institute for Biomedical Research, Cambridge, MA 02142.

© 2008 Hömig-Hölzel et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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