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


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.

SUBMITTER: Choi IK 

PROVIDER: S-EPMC5789919 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Choi Il-Kyu IK   Wang Zhe Z   Ke Qiang Q   Hong Min M   Qian Yu Y   Zhao Xiujuan X   Liu Yuting Y   Kim Hye-Jung HJ   Ritz Jerome J   Cantor Harvey H   Rajewsky Klaus K   Wucherpfennig Kai W KW   Zhang Baochun B  

Proceedings of the National Academy of Sciences of the United States of America 20180108 4


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<sup>+</sup> cytotoxic T cells and a smaller expansion of CD4<sup>+</sup> cells. A major approach to treating EBV-associated lymphomas is adoptive transfer of a  ...[more]

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