HVEM/TNFRSF14 (herpesvirus entry mediator) is a transmembrane protein that is most highly expressed on naïve, memory, and regulatory T cells but declines during T cell activation. It is present at low levels on most resting leukocytes. HVEM is a receptor for BTLA, CD160, and LIGHT. A cis interaction between HVEM and BTLA promotes cell survival, while trans interaction promotes a state of lymphocyte inactivity. LIGHT is expressed following T cell activation and competes with BTLA for HVEM binding, leading to a proinflammatory response. The herpesvirus envelope glycoprotein gD, which binds HVEM to initiate membrane fusion, can antagonize both BTLA and LIGHT binding. Human, but not mouse, HVEM can also bind lymphotoxin-alpha.
