TNFRSF14 - TNF receptor superfamily member 14| Elisa - Clia - Antibody - Protein

Background

TNFRSF14, also known as herpesvirus entry mediator (HVEM), is a member of the tumor necrosis factor receptor superfamily (TNFRSF). Expressed broadly on hematopoietic and non-hematopoietic cells, TNFRSF14 is a transmembrane receptor involved in regulating immune responses. It is a critical component in balancing immune activation and suppression, particularly in T cell regulation, innate immunity, and inflammation. TNFRSF14 interacts with several ligands, including LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160, which engage the receptor in activating or inhibitory roles depending on the context.

Due to its role in immune regulation, TNFRSF14 is significant in autoimmune diseases, cancer, and infectious diseases. For example, in autoimmune diseases like multiple sclerosis, TNFRSF14 signaling can contribute to disease pathology through immune cell activation and inflammation. In oncology, TNFRSF14 can act as an immune checkpoint, modulating anti-tumor immunity, making it a target for potential immunotherapy interventions.

Protein Structure

The structure of TNFRSF14 is characteristic of TNF receptor superfamily members, with specific domains that mediate ligand binding and signaling:

Extracellular Domain (ECD):

• The extracellular portion of TNFRSF14 contains four cysteine-rich domains (CRDs). These CRDs form the ligand-binding sites and facilitate interactions with various ligands, including LIGHT, BTLA, and CD160.
• The four-CRD structure gives TNFRSF14 high flexibility in binding to both TNF family ligands, like LIGHT, and Ig superfamily ligands, such as BTLA and CD160. This structural arrangement allows TNFRSF14 to function in both co-stimulatory and co-inhibitory roles.
• LIGHT binding typically leads to immune activation, while interactions with BTLA and CD160 provide inhibitory signals, a dual capability essential for immune modulation.

Transmembrane Domain (TMD):

• The transmembrane domain of TNFRSF14 anchors it in the cell membrane and connects the extracellular ligand-binding region to the intracellular domain. This single-pass membrane segment facilitates signal transduction by stabilizing the receptor-ligand complexes.

Intracellular Death Domain (DD):

• TNFRSF14 has a death domain (DD) in its cytoplasmic region, characteristic of many TNFRSF members, involved in recruiting intracellular adaptor proteins that mediate downstream signaling.
• This domain is essential for activating various signaling cascades, particularly those involved in NF-κB, MAPK, and PI3K pathways, which regulate immune responses, cell survival, and inflammation.
• The death domain enables the receptor to assemble signaling complexes by binding to intracellular adaptors such as TRAF proteins, leading to either cell activation or apoptotic signaling, depending on the cellular context and ligand engagement.

This structured design enables TNFRSF14 to perform diverse roles by selectively binding different ligands, leading to varied outcomes in immune response regulation.

Classification and Subtypes

TNFRSF14 is classified within the TNF receptor superfamily (TNFRSF). Within this superfamily, TNFRSF14 is distinct in its ability to bind to both TNF superfamily ligands (e.g., LIGHT) and immunoglobulin superfamily ligands (e.g., BTLA and CD160). This ability places TNFRSF14 in a unique position as a bidirectional receptor, where it can function in both stimulatory and inhibitory capacities.

No subtypes of TNFRSF14 exist; however, variations in ligand interactions and co-receptor associations allow TNFRSF14 to exhibit diverse functions based on tissue type, immune cell context, and ligand availability. TNFRSF14 can be categorized functionally as both a co-stimulatory and co-inhibitory receptor, with its role shifting depending on the immune cell types and specific ligands engaged.

Function and Biological Significance

The primary function of TNFRSF14 is to regulate immune responses by acting as both an activator and inhibitor, depending on the ligand and context:

Immune Activation:

• When TNFRSF14 binds to LIGHT, it activates immune cells, particularly T cells and dendritic cells. This interaction promotes the production of pro-inflammatory cytokines and enhances T cell activation, contributing to an anti-pathogen or anti-tumor immune response.
• LIGHT-TNFRSF14 interaction also leads to NF-κB activation, which drives transcription of genes related to inflammation and cell survival, crucial for effective immune responses.

Immune Suppression:

• TNFRSF14 binding to BTLA or CD160 exerts an inhibitory effect on immune cells, especially T cells, promoting immune tolerance and limiting excessive immune responses. This interaction helps maintain immune homeostasis and prevent autoimmune reactions by restraining T cell activation and reducing inflammation.
• Through these inhibitory ligands, TNFRSF14 signaling can prevent overactivation of the immune system, serving as a checkpoint for immune suppression.

Role in Innate and Adaptive Immunity:

• TNFRSF14 modulates both innate and adaptive immune responses. In the innate immune system, its activation via LIGHT can enhance macrophage and dendritic cell responses, supporting the initial stages of immune activation.
• In adaptive immunity, TNFRSF14 on T cells contributes to the regulation of T cell proliferation and differentiation, impacting both T-helper cell responses and cytotoxic T-cell activity.

Maintaining Immune Balance:

• TNFRSF14’s ability to interact with both stimulatory and inhibitory ligands makes it central to maintaining immune balance, particularly in sites of chronic inflammation, such as in tumor microenvironments or autoimmune conditions.
• The receptor’s dual functions make it significant in preventing chronic inflammation and autoimmunity by switching between activation and inhibition, based on ligand binding.

Clinical Issues

TNFRSF14’s role in immune regulation links it to several clinical conditions, including cancer, autoimmune diseases, and infectious diseases:

Cancer:

• In many cancers, TNFRSF14 functions as an immune checkpoint. By engaging with inhibitory ligands like BTLA, TNFRSF14 can suppress anti-tumor immune responses, allowing tumor cells to evade immune surveillance. Inhibiting TNFRSF14-BTLA interactions has thus become a target in cancer immunotherapy, where blocking this interaction could enhance T cell activation against tumors.
• Elevated levels of TNFRSF14 in the tumor microenvironment can inhibit T cell infiltration and activity, leading to immune escape. Drugs targeting TNFRSF14 aim to block these inhibitory signals, thereby boosting the immune response to cancer cells.

Autoimmune Diseases:

• TNFRSF14 has been implicated in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In these conditions, excessive TNFRSF14 signaling with LIGHT promotes chronic inflammation, contributing to disease progression.
• Conversely, blocking TNFRSF14’s interaction with LIGHT could reduce inflammation and prevent tissue damage, highlighting its potential as a therapeutic target for autoimmune diseases. Additionally, targeting TNFRSF14’s inhibitory pathways through BTLA or CD160 might reduce unwanted immune activity, preventing autoimmunity.

Infectious Diseases:

• TNFRSF14 also plays a role in the immune response to infections, particularly in viral infections. For example, herpes simplex virus (HSV) can exploit TNFRSF14 for entry into cells, highlighting the receptor as a potential target for preventing HSV infection.
• The modulation of TNFRSF14 may have therapeutic implications in viral infections where immune responses are either excessively activated or inadequately suppressed, making it a versatile target in infectious disease contexts.

Summary

TNFRSF14 (HVEM) is a multifunctional receptor in the TNF receptor superfamily that balances immune activation and suppression. Structurally, it comprises an extracellular domain with four cysteine-rich regions for ligand binding, a transmembrane domain anchoring it to the cell membrane, and an intracellular death domain responsible for initiating downstream signaling. Through its interactions with both TNF superfamily ligands (like LIGHT) and Ig superfamily ligands (BTLA, CD160), TNFRSF14 acts as a bidirectional immune regulator.

The receptor is significant in multiple biological processes, from promoting immune responses to inhibiting excessive immune activation, and is thus essential for maintaining immune homeostasis. Clinically, TNFRSF14 is linked to various conditions, including cancer, where it can act as an immune checkpoint, and autoimmune diseases, where its interactions with LIGHT contribute to chronic inflammation. Additionally, the receptor’s role in viral entry, particularly for HSV, adds to its relevance in infectious diseases.

Overall, TNFRSF14’s structural adaptability and unique ligand interactions allow it to play diverse roles in immune regulation. Targeting TNFRSF14 and its signaling pathways holds potential for novel therapeutic strategies in immunotherapy, autoimmune disease management, and infectious disease prevention. The receptor’s dual signaling capacity enables a dynamic balance between immune activation and suppression, making it central to immune response modulation across various pathological conditions.