TNFRSF9 - TNF receptor superfamily member 9 | Elisa - Clia - Antibody - Protein

Background

TNFRSF9, also known as 4-1BB or CD137, is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays a key role in immune regulation. This receptor is expressed primarily on activated T cells, as well as on natural killer (NK) cells, dendritic cells, and some other immune cell types, particularly after stimulation. It serves as a co-stimulatory receptor, enhancing T-cell proliferation, survival, and effector function, making it pivotal in immune responses and antitumor immunity.

TNFRSF9 has gained attention as a therapeutic target in cancer immunotherapy due to its role in enhancing immune cell activation and persistence. Upon binding with its ligand, TNFSF9 (also known as 4-1BB ligand or 4-1BBL), TNFRSF9 undergoes trimerization, which is essential for transmitting downstream signaling. This receptor’s functions extend beyond tumor immunity; it is also involved in chronic inflammation and autoimmune diseases, and as such, modulation of TNFRSF9 signaling has therapeutic implications across several pathologies.

Protein Structure

TNFRSF9 has a characteristic protein structure, consistent with other members of the TNF receptor family. The receptor consists of three primary domains: the extracellular, transmembrane, and intracellular (cytoplasmic) domains.

Extracellular Domain:

• The extracellular domain of TNFRSF9 is responsible for ligand binding and consists of four cysteine-rich domains (CRDs) that contribute to structural stability.
• Upon ligand binding, TNFRSF9 undergoes trimerization, a conformational change that is essential for activating its signaling pathways. This trimeric structure is a characteristic shared with other TNF receptors, facilitating the receptor’s co-stimulatory signal transduction.

Transmembrane Domain:

• The transmembrane domain is a hydrophobic alpha-helical segment that anchors TNFRSF9 within the cell membrane. This domain allows the receptor to effectively transmit extracellular ligand interactions to the intracellular signaling domain.

Intracellular (Cytoplasmic) Domain:

• The intracellular domain of TNFRSF9 is relatively short and lacks intrinsic enzymatic activity, a common feature in TNF receptor family members. Instead, this domain recruits intracellular adaptor proteins to initiate signaling cascades.
• Following receptor trimerization, TNFR-associated factor (TRAF) proteins, particularly TRAF1 and TRAF2, are recruited to the cytoplasmic tail. This interaction is crucial for the activation of the downstream signaling pathways, such as NF-κB, MAPK, and JNK, which play vital roles in immune cell activation, survival, and cytokine production.

Classification and Subtypes

TNFRSF9 belongs to the TNF receptor superfamily, which is a large family of receptors involved in diverse cellular processes, including immune modulation, cell survival, and apoptosis. Within this family, TNFRSF9 is classified as a co-stimulatory receptor, differentiating it from other family members that have pro-apoptotic functions, such as TNFR1.

There are no major isoforms of TNFRSF9, though alternative splicing can result in minor variations that impact its functional or regulatory properties. The receptor primarily exists in a trimeric form upon activation, a structure that facilitates efficient signal transduction through TRAF interactions.

Function and Biological Significance

The primary function of TNFRSF9 is to act as a co-stimulatory molecule on immune cells, with significant roles in T-cell activation, proliferation, and effector function. TNFRSF9 activation promotes the survival and function of various immune cells, thus enhancing the immune response, especially in tumor immunity and chronic inflammation.

T-cell Activation and Survival:

• TNFRSF9 is upregulated on T cells following antigen exposure, where it functions as a co-stimulatory receptor that works in conjunction with other signals to enhance T-cell responses.
• Upon ligand binding, TNFRSF9 triggers signaling cascades that activate NF-κB and MAPK pathways, promoting T-cell proliferation, cytokine secretion, and resistance to apoptosis.
• In cancer immunology, TNFRSF9 activation has shown to enhance CD8+ cytotoxic T-cell responses, leading to increased tumor cell killing.

Natural Killer (NK) Cell Activation:

• TNFRSF9 is expressed on NK cells, where it enhances their cytotoxic activity against tumor cells and virally infected cells. This activation is associated with improved cytokine production and increased lysis of target cells, contributing to antitumor immunity.

Dendritic Cell Function:

• In dendritic cells, TNFRSF9 signaling influences antigen presentation and cytokine production, enhancing the ability of these cells to prime T cells effectively. This improves immune surveillance and responsiveness, especially in the context of infections or malignancy.

Regulation of Inflammatory Responses:

• TNFRSF9 plays a dual role in inflammation: while it promotes immune activation, it also contributes to the resolution of inflammation by inducing apoptosis in activated immune cells. This regulatory balance is essential in maintaining immune homeostasis, preventing chronic inflammation and autoimmunity.

Clinical Issues

TNFRSF9 is implicated in several clinical conditions due to its role in modulating immune responses. Aberrant expression or activity of TNFRSF9 contributes to inflammatory diseases, autoimmune disorders, and cancer progression. Therefore, TNFRSF9 serves as a therapeutic target in both oncology and immunology.

Cancer:

• Due to its ability to boost T-cell and NK cell activity, TNFRSF9 is a prominent target in cancer immunotherapy. Agonistic antibodies targeting TNFRSF9 are under investigation for their potential to enhance immune cell-mediated tumor eradication.
• However, overstimulation of TNFRSF9 may lead to immune-related adverse events (irAEs) due to excessive immune activation. Fine-tuning the therapeutic approach is critical to maximize efficacy while minimizing toxicity.

Autoimmune Disorders:

• Dysregulation of TNFRSF9 signaling has been associated with autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. In these conditions, overactivation of TNFRSF9 can lead to prolonged immune cell survival and excessive inflammation.
• Modulating TNFRSF9 activity in autoimmune diseases has therapeutic potential, with strategies focused on reducing immune activation to alleviate disease symptoms and tissue damage.

Infectious Diseases:

• TNFRSF9 is involved in the immune response to viral infections, where it supports T-cell and NK cell function. Enhancing TNFRSF9 signaling can improve immune clearance of viral pathogens, but caution is necessary as overstimulation could lead to excessive inflammation or immunopathology.

Summary

TNFRSF9 (CD137/4-1BB) is a member of the TNF receptor superfamily with critical roles in immune modulation, especially through T-cell, NK cell, and dendritic cell co-stimulation. Its structure includes an extracellular ligand-binding domain, a transmembrane segment, and a cytoplasmic tail that interacts with TRAF proteins to initiate signaling. TNFRSF9 activation enhances immune cell proliferation, survival, and cytokine production, essential for effective antitumor responses and immune regulation.

Clinically, TNFRSF9 is an important target in cancer immunotherapy, where its activation can boost immune responses against tumors. However, this co-stimulatory receptor is also associated with autoimmune and inflammatory diseases when dysregulated. Understanding the complex role of TNFRSF9 in immune regulation continues to guide therapeutic development, with a focus on exploiting its immunostimulatory effects in oncology and mitigating its potential contribution to autoimmunity and chronic inflammatio