TNFRSF1B - TNF receptor superfamily member 1B| Elisa - Clia - Antibody - Protein

Background

TNFRSF1B, also known as Tumor Necrosis Factor Receptor Superfamily Member 1B or TNFR2, is a cell surface receptor predominantly expressed on immune cells, including regulatory T cells (Tregs), endothelial cells, and neurons. TNFR2 is one of the two primary receptors for tumor necrosis factor-alpha (TNF-α), along with TNFR1 (TNFRSF1A). Although TNFR1 and TNFR2 both bind TNF-α, they have unique and overlapping roles within immune responses. TNFR2 primarily activates pathways that promote cell survival, tissue regeneration, and anti-inflammatory responses, differentiating it from TNFR1, which is more commonly associated with apoptosis and pro-inflammatory signaling.

The TNFRSF1B gene is located on chromosome 1p36.22 and encodes a receptor of 461 amino acids. TNFR2 is a key component in regulating inflammation, modulating T cell activity, and contributing to vascular health. Its interaction with TNF-α can activate both canonical (NF-κB) and non-canonical pathways, resulting in varying cellular responses depending on the cellular environment and receptor activation context.

Protein Structure

The TNFRSF1B protein structure is highly specialized for ligand interaction and signaling and consists of three main domains:

Extracellular Domain (ECD):

• The extracellular domain is crucial for ligand binding and contains four cysteine-rich domains (CRDs), each stabilized by disulfide bonds. These CRDs create a structure that allows TNFR2 to bind trimeric TNF-α with high specificity and affinity.
• TNFR2’s ligand-binding architecture is optimized for membrane-bound TNF-α rather than the soluble form, unlike TNFR1, which binds both forms effectively. The preference for membrane-bound TNF-α enables TNFR2 to modulate local immune responses, particularly in immune cell interactions.

Transmembrane Domain (TMD):

• The transmembrane domain, an α-helix, embeds the receptor within the cell membrane, anchoring it between the extracellular and intracellular regions. This domain also contributes to receptor clustering and stability on the cell surface, facilitating efficient signal transduction upon TNF-α binding.

Intracellular Domain (ICD):

• The intracellular domain of TNFR2, while lacking a death domain (which is present in TNFR1), contains regions critical for signaling pathway activation. This region interacts with several adaptor proteins that initiate downstream survival and proliferative pathways.
• TNFR2’s intracellular domain promotes signaling through the canonical NF-κB pathway, activating cell survival genes and cytokine production, and the PI3K/AKT pathway, which supports cellular growth and proliferation.
• Phosphorylation sites in the intracellular domain also regulate interactions with signaling proteins, modulating TNFR2’s effect on immune cells and other TNF-responsive cells.

Classification and Subtypes

TNFRSF1B belongs to the TNF receptor superfamily, characterized by cysteine-rich extracellular domains and their ability to bind members of the TNF ligand superfamily. TNFR2 itself does not have subtypes, but it is functionally and structurally closely related to TNFR1 (TNFRSF1A). While TNFR1 is ubiquitously expressed and activates both cell death and pro-inflammatory pathways, TNFR2 is primarily expressed on immune cells and is more involved in cell survival, immune modulation, and tissue repair.

Function and Biological Significance

The primary role of TNFRSF1B is to mediate cell survival, proliferation, and immune regulation. It serves a unique role in contrast to TNFR1, contributing to the regulation of inflammation without triggering apoptosis. Some of the key functions include:

Cell Survival and Anti-apoptotic Functions:

• TNFR2 activation promotes cell survival by triggering the canonical NF-κB pathway, leading to the expression of anti-apoptotic and pro-survival genes. This activity supports cell viability, particularly in T cells and endothelial cells, and contributes to immune resilience.

Immune Modulation and T cell Activity:

• TNFR2 has a profound role in regulating Treg cells, a subset of T cells crucial for suppressing immune responses and maintaining immune tolerance. TNFR2 activation enhances Treg proliferation and suppressive function, which helps in controlling excessive immune activation and autoimmune responses.
• By supporting Treg activity, TNFR2 plays a role in balancing pro-inflammatory and anti-inflammatory responses, modulating inflammation to prevent tissue damage during immune responses.

Tissue Repair and Regeneration:

• TNFR2 is involved in tissue repair by supporting the survival of endothelial cells and fibroblasts during inflammation. Through the activation of PI3K/AKT and MAPK pathways, TNFR2 promotes cellular proliferation, vascular integrity, and tissue healing.
• This activity is significant in injury sites, where TNFR2-mediated signaling facilitates cellular repair and tissue regeneration processes.

Angiogenesis:

• TNFR2 contributes to angiogenesis, particularly in inflammation and tissue repair. By activating endothelial cells and stimulating the production of angiogenic factors, TNFR2 supports blood vessel formation. This process is essential for wound healing and tissue repair but can also play a role in tumor development when dysregulated.

Immune Cell Interaction and Localized Inflammation:

• Unlike TNFR1, which responds to soluble TNF-α, TNFR2 is specifically activated by membrane-bound TNF-α, often presented by immune cells at inflammation sites. This specificity allows TNFR2 to mediate localized immune responses, activating protective pathways without inducing systemic inflammation.

Clinical Issues

Given its role in immune modulation and cell survival, TNFR2 dysregulation is implicated in various pathological conditions:

Autoimmune and Inflammatory Diseases:

• TNFR2’s role in immune modulation means its dysregulation can lead to inappropriate immune responses. Reduced or impaired TNFR2 signaling has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), and inflammatory bowel disease (IBD).
• In autoimmune diseases, impaired TNFR2 signaling on Tregs leads to reduced immune tolerance and excessive inflammation. TNFR2’s influence on Treg function is a critical area of research for therapeutic strategies in treating autoimmune disorders.

Cancer:

• TNFR2 signaling can have complex effects on cancer. On one hand, TNFR2 activity supports Treg cells, which suppress anti-tumor immunity and could facilitate tumor immune evasion. On the other, TNFR2 promotes endothelial cell and fibroblast survival, aiding in tumor angiogenesis and growth.
• Elevated TNFR2 expression has been noted in various cancers, including lymphoma and melanoma, where it can promote an immunosuppressive tumor microenvironment. Targeting TNFR2 in cancer therapies aims to reduce Treg-mediated immune suppression and improve anti-tumor immune responses.

Cardiovascular Diseases:

• TNFR2’s influence on endothelial cell survival and vascular function implicates it in cardiovascular diseases. Chronic TNFR2 activation, often due to persistent inflammation, can lead to vascular remodeling, contributing to conditions such as atherosclerosis and hypertension.
• In the cardiovascular system, TNFR2 signaling is protective in early atherogenesis stages, but its long-term activation may support plaque formation and contribute to chronic vascular inflammation.

Neurodegenerative Diseases:

• TNFR2 is also involved in neuroinflammation, as it is expressed on microglial cells in the central nervous system (CNS). In neurodegenerative diseases like Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), TNFR2-mediated inflammation may exacerbate neuronal damage and contribute to disease progression.

Summary

TNFRSF1B (TNFR2) is a receptor for membrane-bound TNF-α and mediates cellular responses that promote survival, repair, and immune modulation. Its structure consists of a ligand-binding extracellular domain, a transmembrane domain, and an intracellular signaling domain that lacks a death domain, distinguishing TNFR2 from TNFR1. The primary signaling pathways associated with TNFR2 include the NF-κB pathway and the PI3K/AKT pathway, which support cell survival, proliferation, and inflammation modulation.

TNFR2 plays a crucial role in immune cell interactions, particularly in enhancing the function of regulatory T cells (Tregs) and supporting localized immune responses without widespread inflammation. Clinically, TNFR2 dysregulation is associated with autoimmune diseases, cancer, cardiovascular disease, and neurodegenerative conditions. Therapeutic approaches targeting TNFR2 are being explored, especially for treating autoimmune diseases and certain cancers. By modulating TNFR2 activity, researchers aim to enhance immune tolerance, reduce inflammation, and manage disease progression in various pathologies. TNFR2 remains a target of interest for therapies seeking to balance immune responses while minimizing inflammation-related tissue damage.