LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Dong, Shi; Xu, Xuequn; Plowshay, Julie; Ranheim, Erik A.; Burlingham, William J.; Jensen, Jeffrey L.; Asimakopoulos, Fotis; Tang, Weihua; Gulley, Margaret L.; Cesarman, Ethel; Gumperz, Jenny E.; Kenney, Shannon C.

doi:10.1172/jci76357

Cited by 61 publications

(100 citation statements)

References 51 publications

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“…The ligation of CD40 on B cells with its counter structure on T cells (CD154) elicits bi-directional signaling that is important for B cell activation and differentiation; antibody isotype switch also depends on CD40-CD154 interaction. In EBV-infected B cells the major oncoprotein LMP1 mimics constitutively activated CD40, but recent data suggest that activation signals can still be relayed through CD40 (Ma et al, 2015). In agreement, we observed that incubation of EBV-infected marmoset B cells with a stimulatory anti-CD40 mAb enhances IgG production (own unpublished observation).…”

Section: Treatments Targeting B Cellssupporting

confidence: 84%

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

et al. 2016

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Abstract. The increasing prevalence of chronic autoimmune-mediated inflammatory disorders (AIMIDs) in aging human populations creates a high unmet need for safe and effective medications. However, thus far the translation of pathogenic concepts developed in animal models into effective treatments for the patient has been notoriously difficult. The main reason is that currently used mouse-based animal models for the pipeline selection of promising new treatments were insufficiently predictive for clinical success. Regarding the high immunological similarity between human and non-human primates (NHPs), AIMID models in NHPs can help to bridge the translational gap between rodent and man. Here we will review the preclinical relevance of the experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. EAE is a generic AIMID model projected on the human autoimmune neuro-inflammatory disease multiple sclerosis (MS).

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Section: Treatments Targeting B Cellssupporting

confidence: 84%

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

et al. 2016

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“…Using this model, we recently showed that LMP1 is unexpectedly dispensable for EBV-induced lymphoma formation, since CD40L-expressing human CD4 T cells can partially substitute for LMP1 (38). Our results here suggest that neither LMP1 nor LMP2A is absolutely required for EBV-induced lymphomas in this model, even when both proteins are simultaneously deleted.…”

mentioning

confidence: 56%

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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“…To induce the formation of human B cell lymphomas in vivo, we briefly incubated human umbilical cord blood mononuclear cells (CBMCs) with EBV in vitro to allow viral attachment to the B cells, and then injected the human cells intraperitoneally into NSG mice (34). Using this protocol, typically about 90% of the mice develop tumors that result in mortality within 5 weeks ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…EBV is a human-specific γ-herpesvirus that is associated with several types of human B cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, and posttransplant lymphoproliferative disease (33). A key feature of our model system is that neoplastic transformation of the human B cells occurs in the presence of autologous human T lymphocytes (34). Importantly, the autologous T cells are held in check by PD-1 and CTLA-4, which limit their ability to control the B lymphomas (35).…”

Section: Introductionmentioning

confidence: 99%

Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model

Zumwalde¹,

Sharma²,

Xu³

et al. 2017

JCI Insight

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LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Cited by 61 publications

References 51 publications

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

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

Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model

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LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Cited by 61 publications

References 51 publications

The common marmoset (&lt;i&gt;Callithrix jacchus&lt;/i&gt;): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

The common marmoset (&lt;i&gt;Callithrix jacchus&lt;/i&gt;): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

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

Adoptively transferred Vγ9Vδ2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model

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The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain