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

Significance Epstein–Barr virus (EBV) drives human B cell proliferation and transformation, but also potent T cell surveillance. When surveillance fails, EBV-driven malignancies arise. T cells can be stimulated/expanded on EBV-transformed B cells for adoptive therapy. Clinical data point to the therapeutic importance of CD4 T cells, perhaps through direct cytotoxicity; the mechanism underlying such an activity remains unknown. Previous studies show that signaling by the EBV oncoprotein LMP1 enhances antigen presentation. Here, we show that LMP1+ B cells provide costimulation through CD70 and OX40L to drive cytotoxic CD4 (and CD8) differentiation. In a mouse model of LMP1 (EBV)-driven lymphoma, cytotoxic CD4 cells have superior antitumor activity. These findings provide a mechanism for the EBV-mediated cytotoxic CD4 response and suggest strategies for immunotherapy in EBV-related and other cancers.