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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E686-E695. doi: 10.1073/pnas.1713607115. Epub 2018 Jan 8.

Signaling by the Epstein-Barr virus LMP1 protein induces potent cytotoxic CD4+ and CD8+ T cell responses.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
2
Department of Medicine, Harvard Medical School, Boston, MA 02115.
3
Department of Diagnostics, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
4
Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
5
Department of Cell Biology, Tianjin Medical University, Tianjin 300070, China.
6
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
7
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215.
8
Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany klaus.rajewsky@mdc-berlin.de baochun_zhang@dfci.harvard.edu.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; klaus.rajewsky@mdc-berlin.de baochun_zhang@dfci.harvard.edu.

Abstract

The B-lymphotropic Epstein-Barr virus (EBV), pandemic in humans, is rapidly controlled on initial infection by T cell surveillance; thereafter, the virus establishes a lifelong latent infection in the host. If surveillance fails, fatal lymphoproliferation and lymphomagenesis ensue. The initial T cell response consists of predominantly CD8+ cytotoxic T cells and a smaller expansion of CD4+ cells. A major approach to treating EBV-associated lymphomas is adoptive transfer of autologous or allogeneic T cells that are stimulated/expanded on EBV-transformed B cells. Strikingly, the clinical response correlates with the frequency of CD4 cells in the infused T cells. Although in vitro studies suggested that EBV-specific CD4 cells develop cytotoxicity, they have not been comprehensively characterized and the molecular mechanism underlying their formation remains unknown. Our recent work, using a transgenic approach in mice, has revealed a central role for the EBV signaling molecule LMP1 in immune surveillance and transformation of EBV-infected B cells. The mouse model offers a unique tool for uncovering basic features of EBV immunity. Here, we show that LMP1 expression in B cells induces potent cytotoxic CD4 and CD8 T cell responses, by enhancing antigen presentation and costimulation by CD70, OX40 ligand, and 4-1BB ligand. Our data further suggest that cytotoxic CD4 cells hold superior therapeutic value for LMP1 (EBV)-driven lymphomas. These findings provide insights into EBV immunity, demonstrating that LMP1 signaling alone is sufficient to induce a prominent cytotoxic CD4 response, and suggest strategies for immunotherapy in EBV-related and other cancers.

KEYWORDS:

CD4+ cytotoxic T cells; Epstein–Barr virus; LMP1; costimulatory ligand

PMID:
29311309
PMCID:
PMC5789919
DOI:
10.1073/pnas.1713607115
[Indexed for MEDLINE]
Free PMC Article

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