HVEM (herpesvirus entry mediator) is a type I membrane protein that is TNF receptor superfamily member 14 (TNFRSF14) (1). The mouse HVEM cDNA encodes a 275 amino acid (aa) protein. It contains a 36 aa signal peptide, a 170 aa extracellular domain with three cysteine rich domains (CRD), a 24 aa transmembrane region and a 45 aa cytoplasmic tail with a TRAF interaction domain (1). HVEM expression is highest on naïve, memory and regulatory T cells, but declines during T cell activation (2, 3). It is present at low levels on most resting leukocytes (4). HVEM is a receptor for the IGSF member BTLA (B and T lymphocyte attenuator), CD160, and the TNF family ligand LIGHT (lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes) (2, 9). HVEM and BTLA are constitutively expressed on T cells, while LIGHT is generally considered to be inducible upon TCR activation. In the absence of activation, HVEM and BTLA interact monomerically, either in cis, or in trans. A same cell (or cis) interaction likely promotes general cell survival, while a between cell (or trans) interaction promotes a state of lymphocyte inactivity through the BTLA cytoplasmic domain. Following T cell activation, LIGHT appears and disrupts existing HVEM-BTLA bonds. A LIGHT-HVEM trimer now forms in trans, initiating HVEM-mediated NF kappa B signaling and a proinflammatory response (10). BTLA and LIGHT interactions are not mutually exclusive, but BTLA appears dominant (4, 6, 7). The herpesvirus envelope glycoprotein gD, which binds HVEM CRD1 to initiate membrane fusion, can antagonize both BTLA and LIGHT binding (1, 6, 7, 9). Human, but not mouse, HVEM can also bind lymphotoxin a within CRD2 3 (9, 11). Graft‑vs‑host disease and Th1 type intestinal inflammation can be ameliorated by interrupting T cell LIGHT/HVEM interactions, while disruption of BTLA/HVEM interaction promotes intestinal inflammation (12-14). Mouse HVEM ECD shares 89% and 53% aa identity with rat and human HVEM, respectively. Mouse HVEM can recognize human BTLA and LIGHT, but human HVEM does not recognize mouse ligands (2, 11).