TNFRSF1B

Detailed Information

The TNFRSF1B gene, located at 1p36.22 on the human genome, encodes tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), also commonly known as TNFR2 or CD120b. The gene contains 10 exons and generates multiple mRNA variants, with the predominant isoform encoding a protein of 461 amino acids. TNFRSF1B is classified as a type I transmembrane protein, with an extracellular domain containing four cysteine-rich domains (CRD1–4) that mediate ligand binding to TNF-α and lymphotoxin-α (LT-α). Notably, TNFRSF1B binds TNF-α with much higher affinity (Kd ≈ 10⁻¹⁰ M) than TNFR1 (TNFRSF1A), but it responds preferentially to membrane-bound TNF-α (tmTNF-α) rather than soluble TNF-α. The intracellular region lacks a death domain but harbors a TRAF2-binding motif, which determines its unique downstream signaling compared with TNFR1.

Proteomic studies highlight the importance of post-translational modifications in regulating TNFRSF1B activity. Multiple ubiquitination sites in its cytoplasmic tail mediate interactions with E3 ubiquitin ligases, including cIAP1/2. During T cell activation, TNFRSF1B can undergo proteolytic cleavage to release a soluble form (sTNFR2) that acts as a circulating decoy receptor for TNF-α, conferring immunomodulatory properties. Evolutionary analyses show TNFRSF1B is highly conserved among mammals, with 64% homology between mouse and human proteins, although their expression patterns diverge: mouse TNFR2 is broadly expressed, whereas human TNFR2 is primarily restricted to regulatory T cells (Treg), myeloid cells, and endothelial cells.

Biological Functions and Molecular Mechanisms

TNFRSF1B serves as a key regulatory hub in the TNF-α signaling pathway. By forming heteromeric complexes with TNFR1, it recruits anti-apoptotic proteins such as cIAP1 and cIAP2. These E3 ligases modulate the ubiquitination state of TRAF2, finely tuning the amplitude and duration of NF-κB and MAPK signaling.

NF-κB activation: In the canonical NF-κB pathway, the TRAF2-RIPK1 complex activates the IKK complex, driving degradation of IκBα and nuclear translocation of NF-κB dimers (e.g., p50–RelA), which initiate transcription of survival genes such as BCL2 and BCL2L1 (BCL-XL).

Treg function: In the immune microenvironment, TNFRSF1B signaling is indispensable for regulatory T cell (Treg) stability. The TNF-α–TNFR2 axis enhances Treg proliferation and suppressive activity via PI3K–Akt–mTOR activation, while upregulating immune checkpoint molecules.

Teff regulation: In effector T cells (Teff), TNFRSF1B signaling exerts dual effects: promoting short-term survival through NF-κB activation, but also restraining excessive responses via negative feedback.

Neuroprotection: In neuronal systems, TNFRSF1B stimulates antioxidant pathways such as Nrf2/HO-1, counteracting apoptotic stress. Experimental Parkinson's disease models support its neuroprotective role.

Physiological and Pathological Significance

Normal physiology: TNFRSF1B contributes to immune homeostasis and tissue repair. Knockout mouse models show impaired T cell–dependent antibody responses and reduced clearance of bacterial infections, underscoring its role in adaptive immunity. TNFRSF1B-driven low-level NF-κB activity also helps maintain hematopoietic stem cell (HSC) quiescence, while excessive signaling risks HSC exhaustion.

Autoimmune disease: In rheumatoid arthritis, TNFRSF1B expression is enriched in synovial Tregs, enhancing immunosuppression and alleviating inflammation.

Tumor microenvironment (TME): Malignant cells exploit the TNF-α–TNFR2 axis to expand immunosuppressive Tregs and evade immune surveillance. A 2023 single-cell study in hepatocellular carcinoma (HCC) revealed that resistant tumors upregulate TNFR2 signaling in Tregs through MAIT cell–derived TNF-α, contributing to failure of lenvatinib plus PD-1 antibody therapy.

Hematologic malignancies: In t(8;21) acute myeloid leukemia (AML), m⁶A-dependent transcriptional silencing of TNFRSF1B abrogates its pro-apoptotic signaling, promoting leukemia stem cell survival and self-renewal.

Figure 1. TargetingTNFR2indifferentcellsinthetumormicroenvironment (TME). (Bai J, et al., 2021)

Clinical Research Advances

Autoimmune diseases: TNFR2 antagonists (e.g., MRB-015) are being investigated to block excessive Treg activation. In a phase I trial (NCT04752813), MRB-015 significantly reduced disease activity in rheumatoid arthritis patients (DAS28 reduction ≥1.2) without causing lymphopenia.

Cancer therapy resistance: Clinical data in HCC show elevated TNFRSF1B expression in resistant patients. Preclinical models demonstrate that combining TNFRSF1B-neutralizing antibodies with PD-1 inhibitors reverses Treg-mediated immunosuppression, improving objective response rates.

Hematological disorders: In MDS and AML, TNFRSF1B promoter hypermethylation correlates with poor survival, suggesting value as an epigenetic therapeutic target.

Therapeutic Potential and Challenges

The therapeutic attractiveness of TNFRSF1B lies in its restricted expression profile, contrasting with the ubiquitous TNFR1. This allows selective intervention with reduced systemic toxicity. Current strategies include:

1. Antagonists (antibodies or small molecules) to block TNF-α/TNFR2 signaling and relieve immunosuppression.
2. Agonists (TNFR2-specific antibodies) to selectively stimulate effector T cell activity.
3. Soluble TNFR2-Fc fusion proteins (e.g., etanercept) to neutralize excess TNF-α in inflammatory diseases.

However, several challenges remain:

• The context-dependent duality of TNFRSF1B signaling (pro-Treg vs. pro-Teff) complicates therapeutic strategies.
• Its ligand, tmTNF-α, is membrane-bound, making blockade by conventional antibodies less effective.
• The clinical biomarker potential of sTNFR2 remains uncertain; while elevated in sepsis and GVHD, its predictive value in cancer immunotherapy requires validation.

Looking forward, next-generation bispecific antibodies (e.g., TNFR2/PD-1 dual-targeting) may overcome resistance mechanisms. Moreover, CRISPR-engineered CAR-T cells with TNFR2 enhancement show extended persistence and antitumor activity in preclinical studies. Advances in single-cell multi-omics will further refine our understanding of TNFRSF1B's cell-type–specific roles, paving the way for spatiotemporally precise therapeutic modulation.

Conclusion

As a pivotal TNF receptor family member, TNFRSF1B (TNFR2) finely tunes NF-κB signaling to regulate immune balance, tumor immune evasion, and neuronal survival. While its therapeutic targeting is challenged by biological complexity, TNFRSF1B holds unique promise in reversing immunotherapy resistance and treating hematologic malignancies. Ongoing development of selective modulators and combinatorial strategies will be essential to unlock its clinical potential.