Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion

This report defines a cell surface receptor (OX40) expressed on effector CD 4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo. Sp ecifically, three signals were necessary to promote optimal generation of l ong-lived CD4 T cell memory in vivo: Ag, a danger signal (LPS), and OX40 en gagement, Mice treated with Ag or superantigen (SAg) alone produced very fe w SAg-specific T cells. OX40 ligation or LPS stimulation, enhanced SAg-driv en clonal expansion and the survival of responding T cells. However, when S Ag was administered with a danger signal at the time of OX40 ligation, a sy nergistic effect was observed which led to a 60-fold increase in the number of long-lived, Ag-specific CD4 memory T cells. These data lay the foundati on for the provision of increased numbers of memory T cells which should en hance the efficacy of vaccine strategies for infectious diseases, or cancer , while also providing a potential target (OX40) to limit the number of aut o-Ag-specific memory T cells in autoimmune disease.