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-κB 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.

The Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell-specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including classswitch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBVinfected B cells independent of T cells. IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus that preferentially infects human B lymphocytes. It has adapted to persist in B cells by encoding proteins mimicking cellular proteins that play important roles in B-cell physiology. 1 An example of the latter is the viral latent membrane protein 1 (LMP1), which is considered to be a functional homologue of the CD40 receptor. 2 CD40 is expressed on antigen-presenting cells including B cells, whereas the CD40 ligand (CD40L, CD154) is expressed mainly on activated T cells. The CD40 receptor belongs to the tumor necrosis factor receptor family, containing an extracellular portion with 4 cysteine-rich domains that mediate ligand binding. CD40-CD40L interactions play a crucial role in the T cell-dependent (TD) immune response. CD40 and CD40L knockout mice show defects in the immunoglobulin (Ig) class-switch recombination (CSR), the formation of germinal centers (GCs), somatic hypermutation (SHM) of Ig genes, and the establishment of B-cell memory. 3,4 In vitro stimulation of the CD40 receptor induces proliferation and activation of B cells, and mediates cytokine-dependent CSR. 5 LMP1 shows several functional similarities with the CD40 receptor. Both triggering of the CD40 receptor and LMP1 expression lead to activation, proliferation, and survival of B cells. 6 The intracellular domains of LMP1 and CD40 both interact with tumor necrosis factor receptor-associated factors (TRAFs) and activate overlapping signaling pathways, including extracellular signalrelated kinase (ERK), c-Jun N-terminal kinase (JNK), p38/MAPK, and NFB. 2 However, LMP1 and CD40 do not interact with exactly the same sets of molecules, indicating also some differences in their signaling properties. 7-10 Thus, both LMP1 and CD40 interact directly with TRAFs 1, 2, 3, and 5, but only CD40, and not LMP1, binds directly to TRAF 6. 7,11 Conversely, LMP1, but not CD40, binds to the tumor necrosis factor receptor-associated death domain protein (TRADD) and recept...

The Epstein-Barr virus (EBV) oncoprotein latent membrane protein 1 (LMP1) is thought to act as the major transforming protein in various cell types, by rerouting the tumor necrosis factor receptor family signaling pathway. Despite this implication in EBV-associated transformation of cells, LMP1 toxicity is a well-known but poorly studied feature, perhaps because it contradicts its role in transformation. We show that LMP1 physiological levels are very heterogeneous and that the highest levels of LMP1 correlate with

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