Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.
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.
Hömig-Hölzel
Cornelia
C
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany.
Hojer
Caroline
C
Rastelli
Julia
J
Casola
Stefano
S
Strobl
Lothar J
LJ
Müller
Werner
W
Quintanilla-Martinez
Leticia
L
Gewies
Andreas
A
Ruland
Jürgen
J
Rajewsky
Klaus
K
Zimber-Strobl
Ursula
U
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D018858:Germinal Center / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008223:Lymphoma / Q000503:physiopathology*; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000276:immunology
D019013:CD40 Antigens; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2