Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A

Minamitani, Takeharu; Yasui, Takeshi; Ma, Yijie; Zhou, Hufeng; Okuzaki, Daisuke; Tsai, Chiau-Yuang; Sakakibara, Shuhei; Gewurz, Benjamin E.; Kieff, Elliott; Kikutani, Hitoshi

doi:10.1073/pnas.1514484112

Cited by 44 publications

(37 citation statements)

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“…A number of potential roles for LMP2A in enhancing EBV persistence and/or EBV-associated lymphomas have been proposed, which include regulating the latent-to-lytic switch (45,46), inducing plasma cell differentiation (35), promoting the survival of B cells that have undergone nonproductive BCR rearrangements (21), cooperating with c-Myc overexpression to induce Burkitt-like lymphomas (50,51), and inhibiting the host immune response (52,53). However, many of those previous studies expressed LMP2A at nonphysiological levels and/or were performed outside the context of the intact viral genome.…”

Section: Discussionmentioning

confidence: 99%

“…For example, while LMP2A expression in transgenic mice has been reported to promote autoimmunity and plasma cell differentiation (34,35), and LMP1 expression can lead to lymphomas (11,36), the combination of LMP1 and LMP2A together in transgenic mice normalizes the phenotypes induced by the expression of LMP1 and LMP2A alone (37). Thus, the effects of LMP1 and LMP2A on EBV pathogenesis and B cell biology may be most biologically relevant when studied in the context of the intact virus using models that allow B cells and T cells to interact.…”

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confidence: 99%

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Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Dong

Tsai

Romero-Masters

et al. 2017

J Virol

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Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs) in vitro requires the collaborative effects of EBNA2 (which hijacks Notch signaling), latent membrane protein 1 (LMP1) (which mimics CD40 signaling), and EBV-encoded nuclear antigen 3A (EBNA3A) and EBNA3C (which inhibit oncogene-induced senescence and apoptosis). However, we recently showed that an LMP1-deleted EBV mutant induces B cell lymphomas in a newly developed cord blood-humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand). Here we examined whether the EBV LMP2A protein, which mimics constitutively active B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A delays the onset of EBV-induced lymphomas but does not affect the tumor phenotype or the number of tumors. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset. Nevertheless, the LMP1/LMP2A double mutant induces lymphomas in approximately half of the infected animals. These results indicate that neither LMP1 nor LMP2A is absolutely essential for the ability of EBV to induce B cell lymphomas in the cord blood-humanized mouse model, although the simultaneous loss of both LMP1 and LMP2A decreases the proportion of animals developing tumors and increases the time to tumor onset. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model. IMPORTANCE EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas in vivo in the context of a host immune response. We recently used a newly developed cord blood-humanized mouse model to show that EBV can cooperate with human CD4 T cells to cause B cell lymphomas even when a major viral transforming protein, LMP1, is deleted. Here we examined whether the EBV protein LMP2A, which mimics B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A alone has little effect on the ability of EBV to cause lymphomas but delays tumor onset. The deletion of both LMP1 and LMP2A results in a smaller number of lymphomas in infected animals, with an even more delayed time to tumor onset. These results suggest that LMP1 and LMP2A collaborate to promote early-onset lymphomas in this model, but neither protein is absolutely essential.KEYWORDS EBV, Epstein-Barr virus, LMP1, LMP2A, humanized mouse, lymphoma

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Dong

Tsai

Romero-Masters

et al. 2017

J Virol

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“…In an attempt to overcome this problem, we and others have expressed LMP1 or LMP2A in mouse B cells (13,14,16,(21)(22)(23). Transgenic mice that express LMP1 in B cells develop lymphomas beginning at 12 mo of age (16).…”

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confidence: 99%

“…Expression of LMP2A instead of the BCR allows mouse B cells to circumvent regular B-cell development and to form relatively normal B-cell compartments (13). Conditional expression of LMP2A in mouse GC B cells disturbs affinity maturation and leads to lupus-like symptoms in aged mice (23). More recent studies, in which LMP1 was conditionally expressed in mouse B cells, showed that this single EBV protein is sufficient to provide B cells with the ability to elicit tight T-cell immunosurveillance and, in the absence of immunosurveillance, to proliferate and eventually give rise to B-cell lymphomas (21,22).…”

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confidence: 99%

Mouse model for acute Epstein–Barr virus infection

Wirtz

Weber

Kracker

et al. 2016

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

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Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBVinfected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMPexpressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.pstein-Barr Virus (EBV) is a γ-herpes virus that infects human B cells and growth-transforms them in vitro. Infection is usually asymptomatic, but can lead to infectious mononucleosis (IM) in teenagers and adults (1). EBV drives infected B cells into proliferation, but the symptoms of IM, mainly fever, lymphadenopathy, and splenomegaly, are believed to result from the subsequent activation and massive proliferation of EBV-reactive T cells (2). After the acute phase of infection, EBV persists in a small subset of memory B cells throughout life and is kept in check by memory T cells (2-4). Although an EBV infection is harmless to most people, immunocompromised individuals can develop severe complications. Genetic defects that lead to impaired T-cell function predispose to EBV-driven lymphoproliferative diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) (5, 6). FHL presents in infants and is characterized by persistent fever, hemophagocytosis, and cytokine storms. These symptoms are attributed to proliferation and cytokine production by macrophages and T cells (5-7). About onethird of FHL cases are caused by mutations in the PRF1 gene encoding perforin (8). EBV is also highly associated with HIV-related and posttransplantation lymphomas, which are usually derived from germinal center (GC) B cells. Most likely EBV is the causative agent for these lymphomas, transforming GC B cells when T-cell immunosurveillance is impeded owing to HIV infection or immunosuppressive therapy after organ transplantation (1, 9, 10).The activation and proliferation of EBV-infect...

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“…EBV is associated with multiple cancers including Burkitt lymphoma, nasopharyngeal carcinoma, a subset of gastric cancers, a subset of Hodgkin disease, non-Hodgkin lymphoma localized to the central nervous system, and post-transplant lymphoproliferative disease ( PTLD ) in the context of iatrogenic immunosuppression. Furthermore, EBV is associated with other non-neoplastic diseases including infectious mononucleosis, oral hairy leukoplakia, lupus [3] and X- linked immunodeficiency [4]. These different EBV disease states represent a variety of infected cell types, gene expression states, and levels of host immune activation.…”

Section: Introductionmentioning

confidence: 99%

Animal models of tumorigenic herpesviruses — an update

Dittmer

Damania

Sin

2015

Current Opinion in Virology

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Any one model system, be it culture or animal, only recapitulates one aspect of the viral life cycle in the human host. By providing recent examples of animal models for Epstein Barr Virus and Kaposi Sarcoma-associated Herpesvirus, we would argue that multiple animal models are needed to gain a comprehensive understanding of the pathogenesis associated with human oncogenic herpesviruses. Transgenic mice, homologous animal herpesviruses, and tumorgraft and humanized mouse models all complement each other in the study of viral pathogenesis. The use of animal model systems facilitates the exploration of novel antiviral and anti-cancer treatment modalities for diseases associated with oncogenic herpesviruses.

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Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A

Cited by 44 publications

References 59 publications

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

Mouse model for acute Epstein–Barr virus infection

Animal models of tumorigenic herpesviruses — an update

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