OX40: Structure and function – What questions remain?

•The OX40:OX40L interaction is a key regulator of T cell responses.•OX40L is part of divergent class of TNF superfamily ligands.•OX40 signalling can promote Teffector proliferation as well as inhibit Treg function.•Potential immunotherapeutic target for cancer, inflammatory and autoimmune diseases.•Further understanding of context dependent function will improve clinical outcomes. OX40 is a type 1 transmembrane glycoprotein, reported nearly 30 years ago as a cell surface antigen expressed on activated T cells. Since its discovery, it has been validated as a bone fide costimulatory molecule for T cells and member of the TNF receptor family. However, many questions still remain relating to its function on different T cell sub-sets and with recent interest in its utility as a target for antibody-mediated immunotherapy, there is a growing need to gain a better understanding of its biology. Here, we review the expression pattern of OX40 and its ligand, discuss the structure of the receptor:ligand interaction, the downstream signalling it can elicit, its function on different T cell subsets and how antibodies might engage with it to provide effective immunotherapy.