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.