Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model

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

doi:10.1016/j.cell.2011.12.031

Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model

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

Research output: Contribution to journal › Article › peer-review

118 Citations (Scopus)

Abstract

B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1⁺ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.

Original language	English
Pages (from-to)	739-751
Number of pages	13
Journal	Cell
Volume	148
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2011.12.031
Publication status	Published - Feb 17 2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2011.12.031

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Zhang, B., Kracker, S., Yasuda, T., Casola, S., Vanneman, M., Hömig-Hölzel, C., Wang, Z., Derudder, E., Li, S., Chakraborty, T., Cotter, S. E., Koyama, S., Currie, T., Freeman, G. J., Kutok, J. L., Rodig, S. J., Dranoff, G., & Rajewsky, K. (2012). Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. Cell, 148(4), 739-751. https://doi.org/10.1016/j.cell.2011.12.031

Zhang, B, Kracker, S, Yasuda, T, Casola, S, Vanneman, M, Hömig-Hölzel, C, Wang, Z, Derudder, E, Li, S, Chakraborty, T, Cotter, SE, Koyama, S, Currie, T, Freeman, GJ, Kutok, JL, Rodig, SJ, Dranoff, G & Rajewsky, K 2012, 'Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model', Cell, vol. 148, no. 4, pp. 739-751. https://doi.org/10.1016/j.cell.2011.12.031

@article{acd82c83d8a344589c3d94c1b078a2a5,

title = "Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model",

abstract = "B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.",

author = "Baochun Zhang and Sven Kracker and Tomoharu Yasuda and Stefano Casola and Matthew Vanneman and Cornelia H{\"o}mig-H{\"o}lzel and Zhe Wang and Emmanuel Derudder and Shuang Li and Tirtha Chakraborty and Cotter, {Shane E.} and Shohei Koyama and Treeve Currie and Freeman, {Gordon J.} and Kutok, {Jeffery L.} and Rodig, {Scott J.} and Glenn Dranoff and Klaus Rajewsky",

note = "Funding Information: We thank Dr. S. Cobbold for the anti-CD4, -CD8, and -Thy1 hybridomas; Dr. L. Lanier for the CX5 hybridoma; Dr. R. Schreiber for anti-TNFα (TN3-19.12) and anti-IFNγ (H22) antibodies; Drs. E. Cahir-McFarland and E. Kieff for MSCV-IRES-GFP- and MSCV-LMP1-IRES-GFP-expressing vectors; Dr. D. Raulet for NKG2D −/− mice; Mr. P. Sage and Dr. A. Sharpe for CIITA −/− mice; Drs. U. Basu, F. Meng, and F. Alt for the anti-AID antibody; and Dr. M. Schmidt-Supprian for the J H probe. We thank the NIH Tetramer Facility at Emory University for the PE-conjugated mCD1d-PBS57 tetramer. We are grateful to M. Bamberg, J. Xia, D. Ghitza, C. Grosse, X. Chen, A. Pellerin, J. Grundy, and J. Wang for technical assistance; M. Ottaviano for administrative assistance; S. Koralov for help with sequence analysis and intracellular cytokine staining; S. Peng for HPRT primers; K. K{\"o}chert for advice on statistics; and D. Calado, M. Janz, K. Wucherpfennig, and all Rajewsky lab members for critical comments and suggestions. This work was supported by NIH grants CA098285, CA078378, and AI56299 and a Leukemia and Lymphoma SCOR. B.Z. is supported by a postdoctoral fellowship of the Leukemia and Lymphoma Society. T.Y is supported by a JSPS Postdoctoral Fellowship for Research Abroad and by the Astellas Foundation for Research on Metabolic Disorders. ",

year = "2012",

month = feb,

day = "17",

doi = "10.1016/j.cell.2011.12.031",

language = "English",

volume = "148",

pages = "739--751",

journal = "Cell",

issn = "0092-8674",

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T1 - Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model

AU - Zhang, Baochun

AU - Kracker, Sven

AU - Yasuda, Tomoharu

AU - Casola, Stefano

AU - Vanneman, Matthew

AU - Hömig-Hölzel, Cornelia

AU - Wang, Zhe

AU - Derudder, Emmanuel

AU - Li, Shuang

AU - Chakraborty, Tirtha

AU - Cotter, Shane E.

AU - Koyama, Shohei

AU - Currie, Treeve

AU - Freeman, Gordon J.

AU - Kutok, Jeffery L.

AU - Rodig, Scott J.

AU - Dranoff, Glenn

AU - Rajewsky, Klaus

N1 - Funding Information: We thank Dr. S. Cobbold for the anti-CD4, -CD8, and -Thy1 hybridomas; Dr. L. Lanier for the CX5 hybridoma; Dr. R. Schreiber for anti-TNFα (TN3-19.12) and anti-IFNγ (H22) antibodies; Drs. E. Cahir-McFarland and E. Kieff for MSCV-IRES-GFP- and MSCV-LMP1-IRES-GFP-expressing vectors; Dr. D. Raulet for NKG2D −/− mice; Mr. P. Sage and Dr. A. Sharpe for CIITA −/− mice; Drs. U. Basu, F. Meng, and F. Alt for the anti-AID antibody; and Dr. M. Schmidt-Supprian for the J H probe. We thank the NIH Tetramer Facility at Emory University for the PE-conjugated mCD1d-PBS57 tetramer. We are grateful to M. Bamberg, J. Xia, D. Ghitza, C. Grosse, X. Chen, A. Pellerin, J. Grundy, and J. Wang for technical assistance; M. Ottaviano for administrative assistance; S. Koralov for help with sequence analysis and intracellular cytokine staining; S. Peng for HPRT primers; K. Köchert for advice on statistics; and D. Calado, M. Janz, K. Wucherpfennig, and all Rajewsky lab members for critical comments and suggestions. This work was supported by NIH grants CA098285, CA078378, and AI56299 and a Leukemia and Lymphoma SCOR. B.Z. is supported by a postdoctoral fellowship of the Leukemia and Lymphoma Society. T.Y is supported by a JSPS Postdoctoral Fellowship for Research Abroad and by the Astellas Foundation for Research on Metabolic Disorders.

PY - 2012/2/17

Y1 - 2012/2/17

N2 - B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.

AB - B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.

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JO - Cell

JF - Cell

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ER -

Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model

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