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Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.
Hömig-Hölzel, Cornelia Hojer, Caroline Rastelli, Julia Casola, Stefano Strobl, Lothar J Müller, Werner Quintanilla-Martinez, Leticia Gewies, Andreas Ruland, Jürgen Rajewsky, Klaus
Hömig-Hölzel, Cornelia
Hojer, Caroline
Rastelli, Julia
Casola, Stefano
Strobl, Lothar J
Müller, Werner
Quintanilla-Martinez, Leticia
Gewies, Andreas
Ruland, Jürgen
Rajewsky, Klaus
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2008-06-09
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Abstract
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-kappaB 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.
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Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. 2008, 205 (6):1317-29 J. Exp. Med.
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en
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1540-9538