The LIGHT and DARC sides of herpesvirus entry mediator

Abstract

T he activation of T lymphocytes is finely calibrated by positive and negative signals to allow a vigorous response to invading pathogens while at the same time avoiding the recognition and destruction of the host. Positive signals are delivered through the antigen-specific T cell receptor (TCR) and integrated with additional costimulatory signals. Counteracting these stimulatory effects, inhibitory receptors on lymphocytes serve to limit the response. Viruses have developed counterattacks to the host immune system, interfering with the process of antigen presentation (1) as well as with chemokine and cytokine signals (2). In a recent issue of PNAS, Cheung et al. (3) revealed that two evolutionarily divergent herpes family viruses, Herpes simplex virus (HSV), a member of the α herpes family, and human cytomegalovirus (hCMV), a member of the β herpesvirus family, target the same cosignaling pathway. Cheung et al. show that a previously identified orphan receptor of the TNFR family, UL144, expressed by human CMV, binds to an inhibitory receptor to down-regulate T cell responses. HSV-1 glycoprotein D (gD) binds to the ligand of this same inhibitory receptor and uses it as an entry mediator (4). Two major families of cosignaling receptors participate in modulating the T cell response: the CD28 family and the TNFR superfamily. Whereas engagement of CD28 by its B7 family ligands results in positive signals delivered to T cells, additional CD28 family members contribute positively or negatively to T cell activation (5). Several members of the TNFR family also provide activation and/or survival signals to T cells (6). The TNFR family member herpesvirus entry mediator (HVEM) delivers costimulatory signals to T cells upon binding its TNF family ligand LIGHT (for l ymphotoxin-like, exhibits i nducible expression, and competes with HSV g lycoprotein D for H VEM, a receptor expressed by T lymphocytes) (7). Recently, …