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

Hömig-Hölzel, Cornelia; Caroline, Hojer; Rastelli, Julia; Casola, Stefano; Strobl, Lothar J.; Müller, Werner; Quintanilla-Martı́nez, Leticia; Gewies, Andreas; Ruland, Jürgen; Rajewsky, Klaus; Zimber-Strobl, Ursula

doi:10.1084/jem.20080238

Cited by 116 publications

(148 citation statements)

References 49 publications

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“…Finally, by investigating ex vivo LN samples, we show that the relevant signaling pathways and antiapoptotic Bcl-2 family members are active factors in these proliferation centers. It is known that constitutive CD40 signaling in murine B cells induces alternative NF-kB activation and promotes lymphomagenesis (Homig-Holzel et al, 2008). This correlates well with our finding that prolonged CD40L stimulation of CLL cells (24-72 h) resulted in alternative NF-kB activation and upregulation of Bcl-X L levels.…”

Section: Discussionsupporting

confidence: 91%

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

et al. 2010

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Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavychain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-jB (NF-jB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X L levels, respectively. A dichotomy in NF-jB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X L levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X L and remained chemoresistant. The pivotal contribution of Bcl-X L to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X L levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-jB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X L levels.

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Section: Discussionsupporting

confidence: 91%

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

et al. 2010

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“…By analyzing immunized CD40LTg mice, we demonstrated that GCs grow only up to day 5 in these mice, followed by rapid regression. Early regression of GCs by CD40 signaling is consistent with the previous observation that GC formation is ablated by stimulation with agonistic anti-CD40 Ab or constitutive CD40 signaling (14,17). Although previous studies did not examine the early GC responses, we demonstrated that generation of early GCs up to day 5 is not defective in CD40LTg mice and presented evidence strongly suggesting that early GCs in CD40LTg mice are functional.…”

Section: Discussionsupporting

confidence: 79%

“…To assess in vivo immunological function of CD40L on B cells, we established CD40L transgenic (CD40LTg) mice that constitutively express CD40L on B cells and demonstrated that CD40LTg mice spontaneously develop SLE-like autoimmune disease (13), suggesting that constitutive CD40L expression on B cells has a role in the development of SLE. Recently, Hömig-Hölzel et al (14) established transgenic mice that express EBV latent protein membrane 1/CD40 chimera on B cells that generates constitutive CD40 signaling and demonstrated that these mice develop B cell lymphomas. Thus, CD40 signaling seems to play a crucial role in autoimmunity and leukemogenesis, as well as normal immune responses.…”

mentioning

confidence: 99%

Augmented Antibody Response with Premature Germinal Center Regression in CD40L Transgenic Mice

Kishi

Aiba

Higuchi

et al. 2010

The Journal of Immunology

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Although CD40 signaling is required for activation and differentiation of B cells, including germinal center (GC) formation and generation of memory B cells, in vivo generation of CD40 signaling augments plasma cell differentiation but disrupts GCs. Thus, CD40 signaling is thought to direct B cells to extrafollicular plasma cell fate rather than GC formation. In this study, we analyzed CD40L transgenic (CD40LTg) mice that constitutively express CD40L on B cells. After immunization, activation of B cells, but not dendritic cells, was augmented, although dendritic cells can be activated by CD40 ligation. Bone marrow chimera carrying CD40LTg and nontransgenic B cells showed increased Ab production from transgenic, but not from coexisting nontransgenic, B cells, suggesting that CD40L on a B cell preferentially stimulates the same B cell through an autocrine pathway, thereby augmenting Ab production. Although GCs rapidly regressed after day 5 of immunization and failed to generate late-appearing high-affinity Ab, CD40LTg mice showed normal GC formation up to day 5, as well as normal generation of long-lived plasma cells and memory B cell responses. This observation suggests that CD40 signaling does not block GC formation or differentiation of GC B cells, but it inhibits sustained expansion of GC B cells and augments B cell differentiation.

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“…The heightened activation state caused by LMP1 expression in mice leads to B-cell hyperactivity, resulting in splenomegaly, lymphadenopathy, and production of elevated serum IL-6 and autoantibodies (4). The amplified and constitutive CD40-like signal provided by LMP1 can also contribute to generation of Reed-Sternberg cells (8) and B-cell lymphoma (9).…”

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confidence: 99%

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

Kraus¹,

Nakano

Bishop

2009

Proc. Natl. Acad. Sci. U.S.A.

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The cytoplasmic signaling protein TNF receptor-associated factor 5 (TRAF5) has been implicated in several biological roles in Tlymphocyte responses. However, a clear connection between in vivo TRAF5 immune cell functions and specific signaling pathways has not been made. This study shows that TRAF5 associated strongly with the viral oncogenic CD40 mimic latent membrane protein 1 (LMP1), in contrast to weaker association with CD40, for which it has been shown to play a modest role. LMP1 uses specific TRAFs differently than CD40, resulting in amplified and dysregulated CD40-like activation of B lymphocytes. When the cytoplasmic domain of LMP1 is expressed as a transgenic replacement for CD40 in mouse B cells, the resulting mouse exhibits measures of B-cell hyperactivity such as splenomegaly, lymphadenopathy, elevated serum IL-6, elevated serum autoantibodies, and abnormal splenic architecture. Thus, in contrast to CD40, TRAF5 may have an important nonredundant role as a positive mediator of LMP1 signaling and functions in B cells. To test this hypothesis, mice were created that express mCD40LMP1 in place of CD40, and are either sufficient or deficient in TRAF5. Results revealed that TRAF5 plays a critical role in LMP1-mediated c-Jun kinase signaling and is required for much of the abnormal phenotype observed in mCD40LMP1 transgenic mice. This is the first report showing a major requirement for TRAF5 in signaling by a specific receptor both in vitro and in vivo, as well as playing an important role in biological function in B lymphocytes.B lymphocyte ͉ latent membrane protein 1 ͉ TNF receptor-associated factor ͉ lymphocyte activation ͉ TNF receptor superfamily T he Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a functional mimic of CD40 expressed as a six transmembrane receptor on the cell surface (1). LMP1 selfoligomerizes, resulting in constitutive signaling (1, 2). Although LMP1 can initiate signaling without a ligand, the unique nature of its cytoplasmic domain results in sustained and amplified activation independent of its transmembrane regions. Thus, a hybrid molecule in which the transmembrane domains of LMP1 are replaced with the transmembrane and extracellular portions of CD40 induces B-cell activation that is higher and more prolonged than levels achieved by endogenous CD40 (3-5). Expression of LMP1 by B cells also results in increased survival (5, 6) and class switching (7). The heightened activation state caused by LMP1 expression in mice leads to B-cell hyperactivity, resulting in splenomegaly, lymphadenopathy, and production of elevated serum IL-6 and autoantibodies (4). The amplified and constitutive CD40-like signal provided by LMP1 can also contribute to generation of Reed-Sternberg cells (8) and B-cell lymphoma (9).Like CD40, LMP1 binds and uses cytoplasmic adaptor molecules known as TNF receptor-associated factors (TRAFs). Interestingly, LMP1 uses TRAFs 1, 2, and 3 differently than CD40. TRAFs 1 and 2 cooperate to promote certain CD40-mediated signals to B cells, but TRAF3 inhib...

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

Cited by 116 publications

References 49 publications

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

Augmented Antibody Response with Premature Germinal Center Regression in CD40L Transgenic Mice

TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40

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