TNFSF4 - TNF superfamily member 4 |Elisa - Clia - Antibody - Protein

Background

TNFSF4, also known as OX40 ligand (OX40L) or CD252, is a member of the tumor necrosis factor (TNF) superfamily. It plays a crucial role in the immune system by interacting with the OX40 receptor (CD134), primarily expressed on activated T cells. This interaction contributes to T-cell activation, proliferation, and survival, and it is particularly important for the adaptive immune response. OX40L is predominantly expressed on activated antigen-presenting cells, such as dendritic cells, B cells, and macrophages, and its role in enhancing T-cell function is integral to immune response against infections, cancer, and during inflammatory processes.

OX40L has gained significant attention for its role in immune checkpoint pathways, which are mechanisms that regulate immune response strength and duration. Because of its function in enhancing T-cell activity, it has been studied as a target for immunotherapies in cancer, autoimmune disorders, and infectious diseases. Additionally, dysregulation of the TNFSF4 gene, which encodes OX40L, has been implicated in several inflammatory and autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Protein Structure

OX40L is a type II transmembrane glycoprotein with a structure characteristic of TNF superfamily ligands. Structurally, OX40L contains the following key domains:

Intracellular Domain:

• The intracellular (cytoplasmic) region is relatively short, comprising around 20 amino acids. While limited in size, it plays a role in anchoring the protein to the cell membrane and may be involved in post-translational modifications that influence its stability and function.

Transmembrane Domain:

• OX40L possesses a single transmembrane helix that anchors it in the cell membrane. This domain connects the intracellular domain to the extracellular portion, positioning OX40L for effective interaction with the OX40 receptor on T cells.

Extracellular Domain:

• The extracellular domain of OX40L is the functional component responsible for binding to the OX40 receptor. It consists of a TNF homology domain (THD), which facilitates trimerization—a characteristic shared by other TNF superfamily members. The THD allows OX40L to form a homotrimeric structure, which is necessary for efficient receptor binding and subsequent activation of signaling pathways.
• OX40L is glycosylated at multiple sites within the extracellular domain, contributing to its structural stability and interaction with the OX40 receptor. The glycosylation sites are important for maintaining the functional configuration of the ligand, ensuring its optimal interaction with the receptor and enhancing immune activation.

This trimeric structure of OX40L allows for high-affinity binding to OX40, enabling efficient transduction of co-stimulatory signals that enhance T-cell proliferation and survival. This structural feature is essential for the immune-enhancing role of OX40L and is a key target for therapeutic modulation in diseases requiring immune intervention.

Classification and Subtypes

OX40L is classified as part of the tumor necrosis factor superfamily (TNFSF), specifically as TNFSF4. Within this family, OX40L is one of the ligands involved in immune cell co-stimulation and regulation, alongside other well-known ligands such as CD40L and TNF-α. The TNFSF family members are typically type II transmembrane proteins that form homotrimers, enabling them to efficiently interact with their receptors on target cells. There are no known functional subtypes of OX40L, but its expression is regulated depending on the immune cell type and activation status, which allows for context-specific immune responses.

Function and Biological Significance

The primary function of OX40L is to act as a co-stimulatory molecule in the immune system. Upon binding to OX40 (CD134) on T cells, OX40L initiates several key functions:

T-cell Activation and Survival:

• OX40L-OX40 interaction is essential for the full activation of T cells, particularly CD4+ helper T cells. This interaction provides signals that prevent T-cell apoptosis, extending the survival of activated T cells during immune responses. The OX40L-OX40 axis thus supports the expansion and persistence of T-cell populations, which is critical for effective immune defense.

Enhanced Cytokine Production:

• OX40 signaling enhances the production of cytokines, such as IL-2 and IFN-γ, which support the proliferation and differentiation of T cells. By promoting cytokine secretion, OX40L aids in amplifying immune responses, particularly in the context of infection and tumor immunity.

Regulation of Memory T Cells:

• OX40L is also involved in the generation of memory T cells, which are long-lived cells that provide immunity against previously encountered pathogens. The interaction between OX40L and OX40 is crucial for establishing a memory T-cell pool that can respond rapidly upon re-exposure to antigens.

Interaction with B cells and Dendritic Cells:

• OX40L on antigen-presenting cells like B cells and dendritic cells enhances B-cell function, aiding in antibody production and promoting the presentation of antigens to T cells. This interaction helps to coordinate the adaptive immune response and optimize antibody responses to pathogens.

Tumor Immunity and Inflammatory Responses:

• In the context of cancer, OX40L-mediated co-stimulation is crucial for enhancing anti-tumor T-cell responses. It is considered a potential target for cancer immunotherapy, with the goal of amplifying the T-cell response against tumor cells. Additionally, OX40L plays a role in inflammatory responses, which makes it a key factor in autoimmune diseases and chronic inflammation.

Clinical Issues

The dysregulation of OX40L is associated with a range of clinical conditions, particularly autoimmune diseases, chronic inflammation, and cancer:

Autoimmune Diseases:

• Elevated expression of OX40L has been observed in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Excessive activation of the OX40L-OX40 pathway can lead to overactive T-cell responses and inflammation, exacerbating autoimmune symptoms. Therapeutic interventions aimed at blocking OX40L signaling may help to reduce autoimmune activity and alleviate symptoms in these diseases.

Cancer Immunotherapy:

• Because OX40L enhances T-cell survival and activation, it has been studied as a potential target for cancer immunotherapies. Drugs or antibodies that mimic OX40L signaling or promote OX40L-OX40 interactions could boost T-cell responses against tumor cells, improving outcomes in cancers such as melanoma, lung cancer, and colorectal cancer. However, clinical trials are ongoing, as there are challenges in balancing enhanced immune activation with potential autoimmune side effects.

Inflammatory and Allergic Conditions:

• In diseases with a strong inflammatory component, such as asthma and chronic obstructive pulmonary disease (COPD), OX40L has been implicated in driving excessive immune responses. OX40L inhibitors are being explored as a therapeutic option to control inflammation and reduce symptoms in these patients.

Cardiovascular and Metabolic Diseases:

• Some studies have suggested a link between OX40L levels and cardiovascular diseases, as chronic inflammation contributes to the development of atherosclerosis and other cardiovascular disorders. Modulating OX40L may help in reducing inflammation associated with cardiovascular risk factors, although more research is needed in this area.

Summary

OX40 ligand (OX40L), encoded by the TNFSF4 gene, is a TNF superfamily member involved in immune co-stimulation, enhancing T-cell activation, survival, and memory formation. Structurally, OX40L is a type II transmembrane glycoprotein with an extracellular domain essential for trimeric interaction with the OX40 receptor on T cells. This interaction promotes immune responses by enhancing cytokine production and supporting memory T-cell development, making OX40L essential for both immediate and long-term adaptive immunity.

Dysregulation of OX40L is implicated in autoimmune disorders, cancer, and chronic inflammation, positioning it as a target for immunotherapeutic intervention. In cancer, OX40L-based therapies aim to amplify anti-tumor T-cell responses, whereas in autoimmune diseases, blocking OX40L could mitigate excessive immune activation. Its role in other inflammatory conditions also underscores its potential in treating diseases driven by chronic immune activation. Ongoing research is focused on optimizing OX40L-targeted therapies to enhance efficacy while minimizing side effects, given its broad impact on immune function.