The Role of OX40-Mediated Co-stimulation in T-Cell Activation and Survival

The extent of T-cell activation, proliferation, and survival that follows T-cell receptor (TCR) ligation is controlled by several factors, including the strength of TCR stimulation, the availability of prosurvival cytokines, and the presence or absence of co-stimulatory signals. In addition to engagement of the CD28 costimulatory receptor by its natural ligands, B7.1 (CD80) and B7.2 (CD86), recent work has begun to elucidate the mechanisms by which signaling through the OX40 (CD134) co-stimulatory receptor, a member of the tumor necrosis factor receptor (TNFR) superfamily, affects T-cell responses. Importantly, OX40 ligation has been shown to augment CD4 and CD8 T-cell clonal expansion, effector differentiation, survival, and in some cases, abrogate the suppressive activity of regulatory FoxP3(+)CD25(+)CD4(+) T cells. In this review, we focus on the mechanisms regulating OX40 expression on activated T cells as well as the role of OX40-mediated co-stimulation in boosting T-cell clonal expansion, effector differentiation, and survival.