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Signaling by the Epstein-Barr virus LMP1 protein induces potent cytotoxic CD4 + and CD8 + T cell responses.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Jan 23; Vol. 115 (4), pp. E686-E695. Date of Electronic Publication: 2018 Jan 08. - Publication Year :
- 2018
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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 <superscript>+</superscript> cytotoxic T cells and a smaller expansion of CD4 <superscript>+</superscript> 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.<br />Competing Interests: Conflict of interest statement: I.-K.C., Z.W., and B.Z. have filed patent applications on aspects of this research.
- Subjects :
- 4-1BB Ligand metabolism
Animals
B-Lymphocytes metabolism
CD27 Ligand metabolism
Lymphoma virology
Mice, Inbred BALB C
Mice, Inbred C57BL
OX40 Ligand metabolism
T-Box Domain Proteins metabolism
CD4-Positive T-Lymphocytes physiology
CD8-Positive T-Lymphocytes physiology
Herpesvirus 4, Human immunology
Lymphoma immunology
Viral Matrix Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29311309
- Full Text :
- https://doi.org/10.1073/pnas.1713607115