1. Signaling by the Epstein–Barr virus LMP1 protein induces potent cytotoxic CD4+ and CD8+ T cell responses
- Author
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Harvey Cantor, Zhe Wang, Hye-Jung Kim, Klaus Rajewsky, Min Hong, Xiujuan Zhao, Jerome Ritz, Qiang Ke, Il-Kyu Choi, Kai W. Wucherpfennig, Baochun Zhang, Yuting Liu, and Yu Qian
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Adoptive cell transfer ,Herpesvirus 4, Human ,Lymphoma ,medicine.medical_treatment ,T cell ,Antigen presentation ,OX40 Ligand ,Biology ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Virus ,Viral Matrix Proteins ,03 medical and health sciences ,hemic and lymphatic diseases ,medicine ,Cytotoxic T cell ,Animals ,B-Lymphocytes ,Mice, Inbred BALB C ,Multidisciplinary ,Immunotherapy ,Epstein–Barr virus ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,4-1BB Ligand ,PNAS Plus ,Cancer research ,T-Box Domain Proteins ,CD8 ,CD27 Ligand - 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.
- Published
- 2018