TNFRSF4 - TNF receptor superfamily member 4 | Elisa - Clia - Antibody - Protein

Background

TNFRSF4, commonly known as OX40 (CD134), is a member of the tumor necrosis factor receptor (TNFR) superfamily. It is an important costimulatory molecule expressed on T cells, specifically induced upon T cell activation. TNFRSF4 is known for its involvement in regulating immune responses, especially in T-cell proliferation, survival, and memory formation. As an immune-regulatory receptor, it primarily interacts with its ligand, OX40L (TNFSF4), which is expressed on antigen-presenting cells (APCs), such as dendritic cells, B cells, and macrophages.

OX40’s role in immune modulation is significant because it amplifies T-cell responses during both acute infections and in chronic immune responses, such as autoimmune diseases and cancer. By sustaining T-cell activation and enhancing immune memory, OX40 has become a central target in immunotherapy research, especially in the contexts of cancer immunotherapy and autoimmune diseases. Its ability to promote prolonged immune responses also makes it a critical regulator in various immune-related diseases, where modulation of OX40-OX40L interactions can potentially benefit patient outcomes.

Protein Structure

TNFRSF4/OX40 is a type I transmembrane protein with a structure that includes several domains essential for its function in immune cell signaling:

Extracellular Domain:

• The extracellular domain of OX40 is approximately 200 amino acids in length and contains four cysteine-rich domains (CRDs) that are characteristic of TNF receptor family members. These CRDs are important for ligand binding, stability, and signal transduction.
• The CRDs facilitate the binding of OX40 to its ligand, OX40L, forming a trimeric complex that stabilizes interactions between OX40 and immune cells. These cysteine-rich regions are stabilized by disulfide bonds, which provide structural integrity, enabling OX40 to effectively transmit signals upon ligand binding.
• The extracellular region also includes N-glycosylation sites, which are essential for protein folding, stability, and cell-surface expression. This glycosylation helps in the receptor-ligand interactions that initiate downstream signaling cascades.

Transmembrane Domain:

• Following the extracellular domain is the transmembrane region, which anchors OX40 to the T cell membrane. The transmembrane region consists of approximately 20 hydrophobic amino acids that span the cell membrane, providing structural support for the receptor and facilitating signal transduction upon ligand binding.

Intracellular/Tail Domain:

• The intracellular (or cytoplasmic) domain is shorter than the extracellular region but is crucial for signal transduction. It includes TNFR-associated factor (TRAF) binding motifs, which recruit signaling adaptor proteins necessary for downstream signal activation.
• The TRAF binding sites specifically interact with TRAF2, TRAF3, and TRAF5, facilitating signal pathways that activate nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and other signaling molecules. These pathways are crucial for T-cell survival, proliferation, and differentiation into memory cells.

Classification and Subtypes

OX40 is classified within the TNF receptor superfamily (TNFRSF), specifically known as TNFRSF4. It is distinct from other family members based on its expression pattern, ligand specificity, and role in T-cell immune responses. There are no major subtypes of OX40 itself, but it is closely associated with other TNFRSF members like 4-1BB (TNFRSF9) and GITR (TNFRSF18), which share functional roles in immune costimulation. OX40’s ligand, OX40L, is the primary ligand that interacts with it to trigger downstream signaling; however, some alternative interactions with other receptors are explored in immune-modulatory pathways, particularly in the tumor microenvironment.

Function and Biological Significance

OX40 functions as a costimulatory molecule and plays a critical role in sustaining and amplifying immune responses:

T-Cell Activation and Survival:

• Upon antigen recognition, T cells express OX40, which binds OX40L on APCs to enhance T-cell activation. This binding interaction promotes T-cell survival by inducing anti-apoptotic pathways, mainly through activation of NF-κB, which upregulates survival proteins.
• OX40 signaling supports prolonged T-cell activity, which is essential for effective immune responses in infections and vaccinations, allowing for the expansion and persistence of effector and memory T cells.

Formation of Memory T Cells:

• OX40’s role in the formation of memory T cells is critical for long-lasting immunity. By engaging in prolonged T-cell receptor (TCR) signaling, OX40 supports the differentiation of effector T cells into memory cells. This memory T-cell pool is essential for rapid and robust responses upon subsequent encounters with pathogens.

Modulation of Tregs (Regulatory T Cells):

• Interestingly, OX40 can also influence regulatory T cells (Tregs). While OX40 generally promotes pro-inflammatory T-cell responses, its expression on Tregs has been shown to modulate their suppressive function, sometimes reducing Treg-mediated suppression, which can enhance effector T-cell responses.
• This regulation of Tregs is particularly relevant in cancer and autoimmune contexts, where modulation of immune suppression and activation can either enhance anti-tumor immunity or exacerbate autoimmune pathology.

Tumor Immunology:

• OX40 has become a target in cancer immunotherapy due to its ability to potentiate T-cell responses against tumor antigens. Stimulation of OX40 can enhance T-cell proliferation, cytotoxicity, and resistance to apoptosis, which are beneficial for eliminating tumor cells.
• OX40 agonists, often antibodies that bind and activate OX40, are currently being investigated in clinical trials as potential cancer immunotherapies. These agents aim to boost anti-tumor immune responses by promoting T-cell activation and memory formation.

Clinical Issues

OX40 signaling is implicated in a variety of immune-mediated conditions due to its central role in T-cell activation and memory formation:

Autoimmune Diseases:

• Enhanced OX40 signaling can exacerbate autoimmune diseases by promoting prolonged and excessive T-cell responses. Overactivity of OX40 has been linked to autoimmune conditions like rheumatoid arthritis, multiple sclerosis, and lupus, where inappropriate immune responses lead to tissue damage.
• Therapeutic strategies targeting OX40-OX40L interactions in autoimmune diseases aim to dampen excessive T-cell responses to prevent autoimmunity. Antagonists of OX40 are being explored to reduce inflammation and limit disease progression in these conditions.

Cancer Immunotherapy:

• OX40 agonists are of significant interest in cancer immunotherapy. Preclinical and clinical studies indicate that OX40 stimulation enhances anti-tumor immunity by increasing T-cell infiltration, activation, and survival within the tumor microenvironment.
• Clinical trials of OX40 agonistic antibodies are being conducted in various cancers, including melanoma, non-small cell lung cancer, and ovarian cancer. Early results suggest that OX40 agonists can improve patient outcomes, especially when combined with other immune checkpoint inhibitors.

Infectious Diseases:

• The role of OX40 in prolonging immune responses makes it a potential target for enhancing immunity in chronic infections, such as HIV and hepatitis C. By boosting T-cell persistence, therapies targeting OX40 could improve the immune system’s ability to control chronic infections.

Organ Transplantation:

• In the context of organ transplantation, modulation of OX40 signaling can be critical for preventing transplant rejection. OX40-OX40L blockade may reduce the activity of effector T cells that mediate graft rejection, thereby improving transplant tolerance and success rates.

Summary

TNFRSF4, also known as OX40, is a TNF receptor superfamily member with vital roles in T-cell activation, survival, and memory formation. Structurally, it is a type I transmembrane protein with an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain that facilitates signaling. OX40 primarily binds to its ligand OX40L on APCs, promoting T-cell activation and sustaining immune responses, particularly in effector and memory T cells. This function is crucial in fighting infections, establishing immune memory, and enhancing immune responses in cancer.

In clinical contexts, OX40 has therapeutic implications across autoimmune diseases, cancer, chronic infections, and organ transplantation. The modulation of OX40 signaling can either enhance immune responses (e.g., in cancer) or dampen them (e.g., in autoimmunity), depending on the therapeutic goals. Current research is actively investigating OX40-targeted therapies, especially in cancer immunotherapy, with promising early results showing that OX40 agonists can improve T-cell-mediated tumor immunity.