Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model

Zhang, Baochun; Kracker, Sven; Yasuda, Tomoharu; Casola, Stefano; Vanneman, Matthew W.; Hömig-Hölzel, Cornelia; Wang, Zhe; Derudder, Emmanuel; Li, Shuang; Chakraborty, Tirtha; Cotter, Shane E.; Koyama, Shohei; Currie, Treeve; Freeman, Gordon J.; Kutok, Jeffery L.; Rodig, Scott J.; Dranoff, Glenn; Rajewsky, Klaus

doi:10.1016/j.cell.2011.12.031

Cited by 145 publications

(186 citation statements)

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“…None of these targets were killed by T cells isolated from CD19-Cre ERT2 ; hCD2 flSTOP mice 8 d after tamoxifen treatment. These results indicate that the activated CD8 T cells kill LMP-driven B-cell blasts in an antigen-specific, MHCrestricted manner in line with our earlier data on T-cell surveillance of LMP1-induced B-cell lymphomas in the mouse (21) and data from the human (25).…”

Section: Reviewerssupporting

confidence: 77%

“…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). Although earlier in vivo studies have offered insights into the role of LMP1 as an oncogene and of LMP2A as a BCR surrogate, little attention has been paid to the immune response against LMP-expressing B cells.…”

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confidence: 99%

“…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%

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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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confidence: 77%

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confidence: 99%

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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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“…Experimental models have shown a central role for CD8 + T cells in protective immunity to EBV. 15,16 Longitudinal analyses of lymphocyte cytotoxicity in the patient demonstrated an absence of exocytosis and cytotoxicity by both CTL and NK cells ( Figure 3B,C), which was partially restored by IL-2 stimulation ( Figure 3D,E). Relative to a healthy control, EBV-specific T cells in the patient produced TNF-α, but displayed impaired degranulation in response to BZLF-1 peptides ( Figure 3F).…”

Section: Resultsmentioning

confidence: 98%

Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations

et al. 2012

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“…Together with LMP1, which constitutively activates CD40 signaling (19,20), LMP2A may provide a survival advantage for EBV-infected B cells by modifying GC B-cell selection. However, B-lineage-specific expression of LMP1 inhibits GC formation (20) or causes B-cell ablation through immune surveillance (21). LMP2A does not affect affinity maturation of B cells in GCs when expressed in B cells of a transgenic mouse line (22).…”

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confidence: 99%