TNFSF14

Detailed Information

The TNFSF14 gene is located on human chromosome 19p13.3 and encodes a type II transmembrane protein known as LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for HVEM binding). The gene contains four exons and produces two major isoforms through alternative splicing: a full-length membrane-bound form (LIGHT-α) and a soluble form lacking the transmembrane domain (LIGHT-β). Structurally, LIGHT is a typical member of the tumor necrosis factor (TNF) superfamily, with an extracellular TNF homology domain (THD) that binds receptors as a trimer. The full-length LIGHT protein has a molecular weight of 29 kDa, reaching 35–40 kDa after glycosylation, while the soluble form is generated by proteolytic cleavage mediated by metalloproteinases such as ADAM17.

LIGHT interacts with a complex network of receptors. Its primary receptor is TNFRSF14/HVEM (herpesvirus entry mediator), while secondary receptors include TNFRSF3/LTβR (lymphotoxin β receptor) and the decoy receptor TNFRSF6B/DcR3. HVEM functions as a bidirectional signaling molecule in immune regulation. When acting as a receptor for LIGHT, HVEM transmits co-stimulatory signals to activate lymphocytes. Conversely, HVEM itself can serve as a ligand for BTLA (B and T lymphocyte attenuator) and CD160, delivering inhibitory signals. This dual functionality positions the HVEM-LIGHT axis as a critical regulatory hub in the immune system.

Expression analysis shows that TNFSF14 is highly expressed in activated T cells, natural killer (NK) cells, dendritic cells (DCs), and granulocytes, while resting lymphocytes exhibit low expression. LIGHT is enriched in lymphoid tissues such as the spleen, lymph nodes, and Peyer's patches, as well as in sites of inflammation. HVEM is widely expressed in naive CD4+ T cells, CD8+ memory T cells, regulatory T cells (Tregs), dendritic cells, monocytes, and neutrophils, providing a structural basis for intercellular communication.

Bidirectional Immune Regulation

The LIGHT-HVEM interaction mediates bidirectional regulation in the immune system. In forward signaling, LIGHT functions as a co-stimulatory molecule to activate T cell responses. Upon recognition of antigen-presenting cells (APCs) by the T cell receptor (TCR), LIGHT binding to HVEM recruits TRAF2/5 adaptor proteins, activating NF-κB and MAPK pathways, promoting IL-2 and IFN-γ secretion and T cell proliferation. Conversely, when HVEM serves as a ligand for BTLA or CD160, inhibitory signals are transmitted. BTLA contains intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit SHP-1/2 phosphatases upon phosphorylation, negatively regulating TCR signaling. This balance ensures immune homeostasis, with LIGHT-HVEM promoting effector T cell activity and HVEM-BTLA restraining excessive activation. In germinal centers, LIGHT expressed by follicular helper T cells (Tfh) binds HVEM on B cells to support proliferation and antibody production, while B cell BTLA expression provides negative feedback to prevent overactivation.

Figure 1. LIGHT(TNFSF14) and its Three Receptors: HVEM, LTBR and DcR3. (Mousa RS, et al., 2025)

Antimicrobial Immunity

LIGHT plays a unique role in antiviral immunity. HVEM, originally identified as a receptor for herpes simplex virus (HSV) entry, mediates viral fusion via glycoprotein gD. Endogenous LIGHT competes with gD for HVEM binding, blocking HSV infection and demonstrating broad antiviral activity. LIGHT also enhances adaptive immunity by activating dendritic cells and promoting CD8+ T cell memory formation. In bacterial infections, LIGHT contributes to intestinal mucosal immunity. Intestinal epithelial cells constitutively express HVEM, while intraepithelial lymphocytes express LIGHT and CD160. LIGHT-HVEM interaction activates NF-κB, inducing antimicrobial peptides such as β-defensins and strengthening barrier function. Overexpression of LIGHT in mouse intestinal epithelium enhances resistance to bacterial infection, whereas LIGHT deficiency impairs bacterial clearance and exacerbates inflammation.

Regulation of Cell Apoptosis

LIGHT selectively induces apoptosis in tumor cells. The binding of LIGHT to LTβR on tumor surfaces activates the extrinsic apoptotic pathway via FADD-caspase8 signaling. In multiple tumor cell lines, recombinant LIGHT treatment induces significant apoptosis while sparing normal epithelial cells. In the liver, LIGHT exhibits dual regulatory effects, promoting apoptosis in hepatocellular carcinoma cells while protecting normal hepatocytes from TNF-α-induced death through PI3K-Akt activation and upregulation of anti-apoptotic proteins, maintaining tissue homeostasis.

Lymphoma Development

Mutations in TNFSF14 or HVEM are frequent in germinal center-derived B cell lymphomas. Loss-of-function mutations in HVEM remove inhibitory control over B cells, promoting overproliferation. Simultaneously, LIGHT overstimulation of LTβR-NF-κB signaling drives cell survival. Mouse models with B cell-specific HVEM deletion show accelerated germinal center B cell proliferation and spontaneous lymphoma formation, whereas soluble HVEM administration mitigates this effect.

Autoimmunity and Inflammation

The LIGHT-HVEM axis is hyperactive in autoimmune conditions. Elevated LIGHT expression in rheumatoid arthritis synovial tissue originates from infiltrating CD4+ T cells and macrophages, contributing to joint damage through fibroblast activation, osteoclast differentiation, and inflammatory cytokine cascades. In inflammatory bowel disease, increased LIGHT levels correlate with disease activity, promoting fibrosis and epithelial barrier disruption. Targeting LIGHT in experimental models reduces tissue damage and fibrotic responses, highlighting therapeutic potential.

Organ Transplant Rejection

LIGHT contributes to graft injury in transplant rejection. Recipient CD8+ T cell-derived LIGHT binds HVEM on graft endothelial cells, activating NF-κB and AP-1, upregulating adhesion molecules, and promoting lymphocyte infiltration. LIGHT also induces chemokine secretion, amplifying inflammation. In chronic rejection, LIGHT-mediated LTβR signaling drives vascular smooth muscle proliferation and intimal hyperplasia. Therapeutic interventions targeting LIGHT or its receptors can reduce graft damage and modulate immune tolerance.

Clinical Applications and Translational Research

Soluble LIGHT (sLIGHT) levels serve as markers of inflammatory activity. Elevated sLIGHT correlates with disease severity and may predict treatment response in various conditions, providing potential guidance for therapeutic monitoring.

Therapeutic strategies targeting the LIGHT-HVEM axis include LIGHT-neutralizing antibodies, HVEM-Fc fusion proteins acting as decoy receptors, BTLA agonists to enhance inhibitory signaling, and nucleic acid aptamers that selectively block LIGHT in tissues. These approaches aim to modulate immune responses in autoimmune diseases, transplant rejection, and inflammatory conditions.

LIGHT modulates the tumor microenvironment by activating dendritic cells, promoting tertiary lymphoid structure formation, and reversing T cell exhaustion. Local administration of LIGHT-expressing viral vectors enhances anti-tumor immunity and shows synergistic effects when combined with immune checkpoint inhibitors. Gene therapy approaches targeting HVEM mutations, such as CAR-T cells expressing wild-type HVEM, are under investigation in preclinical models.

Research Challenges and Future Directions

Understanding the LIGHT-HVEM-BTLA network faces challenges due to bidirectional signaling, complex roles of soluble receptors, and receptor crosstalk. Translational obstacles include tissue-specific delivery and minimizing systemic immunosuppression. Emerging strategies involve smart delivery systems, bispecific antibodies, and synthetic biology approaches such as tumor-restricted LIGHT activation. Future research will focus on structural insights, microenvironment-responsive therapeutics, and engineered immune cells to harness LIGHT's multifunctional regulatory potential.