HVEM is found on the surface of various cell types, including hematopoietic and non-hematopoietic cells, and is expressed mainly in spleen, thymus, bone marrow, lung and intestines. It has been identified as a canonical TNF receptor, signaling through the TNF receptor-associated factors (TRAFs) leading to NF?B activation. Furthermore, in addition to acting as a signaling receptor, in binding to Ig superfamily members it acts as a ligand for these inhibitory receptors. Therefore, bidirectional signaling is possible for the HVEM-mediated signaling network, which can be involved in positive or negative immunological reactions under different contexts.