Targeting OX40 and OX40L for the treatment of autoimmunity and cancer.

The optimal activation of naïve T cells requires TCR-mediated recognition of cognate peptide-MHC complexes on antigen presenting cells in the presence of costimulatory signals. Although signals provided via CD28-B7 interactions are important for enhancing the initial T-cell response, other costimulatory signals are required for sustaining the response and promoting both T-cell differentiation and survival. In particular, engagement of OX40 (CD134) by its natural ligand OX40L (CD134L) or OX40 agonists has been shown to provide key signals that can augment CD4 and CD8 T-cell responses. Importantly, numerous studies have highlighted the ability of OX40-specific agonists or antagonists to enhance antitumor immunity or ameliorate autoimmune disease, respectively. On the basis of these studies, the development of OX40- and OX40L-specific reagents has been pursued for clinical use. Given the emerging role of OX40 and OX40L as novel therapeutic targets, this review will focus on the cellular and molecular mechanisms of OX40-mediated T-cell costimulation with a special emphasis on the role of OX40-OX40L interactions in the etiology and treatment of autoimmunity and cancer.