In Epstein-Barr virus (EBV)-related lymphomas, EBV oncoprotein LMP1 upregulates MHC class I and class II molecules and costimulatory ligands CD70, OX40L, and 4-1BBL on the cancer cell surface, allowing LMP1+ B cells to act as antigen-presenting cells and directly prime cytolytic CD4+ and CD8+ T cell responses. Further, CD70 and OX40L drive the differentiation of CD4+ T cells towards an Eomes-programmed (Granzyme-B producing) cytotoxic state, while CD70, OX40L, and 4-1BBL all contribute to the Eomes-programming of CD8+ T cells.
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.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (2) Department of Medical Onco
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Diagnostics, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Cell Biology, Tianjin Medical University, Tianjin 300070, China. (7) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215. (11) Immune Regulation and Cancer, Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany klaus.rajewsky@mdc-berlin.de baochun_zhang@dfci.harvard.edu. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; klaus.rajewsky@mdc-berlin.de baochun_zhang@dfci.harvard.edu. Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215.
