TNFRSF14

TNFRSF14 Full Name

tumor necrosis factor receptor superfamily, member 14

TNFRSF14 Introduction

TNFRSF14 or Herpesvirus Entry Mediator (HVEM) is a type I transmembrane protein belonging to the TNF receptor superfamily. TNFRSF14 was so named the Herpesvirus Entry Mediator because it was originally identified as a receptor that herpesvirus family of viruses utilize to enter their host cell. TNFRSF14 can serve as a signaling receptor or a ligand itself on a cell and has been referred to as a complex immune checkpoint molecule that can bind to multiple distinct ligands (LIGHT, BTLA and CD160) to provide a fine-tuned balance between activation and inhibition.

In its role as a receptor, when TNFRSF14 binds to its ligand LIGHT, it transmits a costimulatory signal. This is primarily achieved through the activation of the NF-κB signaling pathway, leading to the promotion of T-cell activation, proliferation, and the production of pro-inflammatory cytokines, ultimately enhancing the immune response. This activating signal plays a role in anti-tumor immunity and pathogen clearance. In its role as a ligand, TNFRSF14 binds to inhibitory receptors BTLA or CD160 expressed on the surface of T cells or other immune cells, transmitting a potent inhibitory signal. This inhibitory signal is primarily mediated by the recruitment of phosphatases such as SHP-1 and SHP-2 to the intracellular domains of BTLA or CD160. This subsequently inhibits the T-cell receptor (TCR) signaling pathway, leading to the suppression of T-cell function. This mechanism contributes to immune tolerance and the prevention of autoimmune responses.

Figure 1. Molecular model of the activating and inhibitory pathways of HVEM. (Source: Steinberg MW, et al. 2011)

Loss of function of TNFRSF14 is strongly associated with human diseases, especially autoimmune diseases and tumors. So far, TNFRSF14 mutations or SNPs have been verified by GWAS or genetic studies to be highly associated with the susceptibility of various autoimmune diseases, such as MS, RA, IBD and so on. In oncology, TNFRSF14 is considered to be a promising target for cancer immunotherapy. Depending on the expression pattern and the dominant ligands in the tumor microenvironment (TME), TNFRSF14 may be pro-tumorigenic through promotion of anti-tumor immunity by LIGHT signaling or anti-inflammatory through the BTLA/CD160 inhibitory pathway.

Alternate Names for TNFRSF14

TNFRSF14; tumor necrosis factor receptor superfamily, member 14; tumor necrosis factor receptor superfamily, member 14 (herpesvirus entry mediator); tumor necrosis factor receptor superfamily member 14; ATAR; CD270; herpesvirus entry mediator; HVEA; HVEM; LIGHTR

• 1. Steinberg MW, et al. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011 Nov;244(1):169-87.
  2. Wojciechowicz K, et al. The role of the BTLA-HVEM complex in the pathogenesis of autoimmune diseases. Cell Immunol. 2022 Jun;376:104532.