Herpes virus entry mediator (HVEM), also known as TNFR superfamily 14 (TNFRSF14), is a type I transmembrane protein expressed on most hematopoietic cells including B cells, T cells, NK cells, dendritic cells (DC), and myeloid cells, as well as non-lymphoid organs including lung, liver, and kidney. To date, five molecules have been reported to interact with HVEM; glycoprotein D (gD) of herpes simplex virus origin, trimeric lymphotoxin alpha (LTα), LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed on T lymphocytes), B and T lymphocyte attenuator (BTLA), and CD160. Upon ligation, immune signals are delivered to HVEM and/or HVEM can induce signals through its "ligands," employing a mechanism termed reverse signaling. Signaling through HVEM recruits TNF receptor-associated factor (TRAF) 1, 2, 3, and 5, inducing activation of NF-κB and JNK/AP-1 pathways. HVEM signal mediates potent T cell co-stimulatory effects, which enhances proliferation, Th1-type cytokine production, and survival of T cells. Consistent with these effects, upregulation of HVEM signal facilitates tumor-reactive T cell activation and leads to cancer regression as well as protective antitumor immunity.
Park J-J, Anand S, Zhao Y, et al. Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory. Cancer immunology, immunotherapy?: CII. 2012;61(2):203-214.