TNFRSF8 - TNF receptor superfamily member 8 |Elisa - Clia - Antibody - Protein

Background

TNFRSF8 (Tumor Necrosis Factor Receptor Superfamily Member 8), also known as CD30, is a cell surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily. This family is composed of receptors that play critical roles in modulating immune responses, inflammation, and apoptosis. CD30 is primarily expressed on activated T and B cells, and its expression is upregulated in certain immune-related diseases and cancers, particularly Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). It has emerged as a significant target in cancer immunotherapy and as a diagnostic marker for lymphoma.

The receptor is a hallmark of classical Hodgkin lymphoma (cHL) and ALCL due to its overexpression on malignant cells. Beyond cancer, CD30 has implications in the regulation of immune homeostasis, playing a role in T-cell activation, differentiation, and proliferation. Dysregulation of CD30 signaling can lead to chronic inflammation and the development of autoimmune disorders, making it an essential molecule of interest in both oncology and immunology.

Protein Structure

The TNFRSF8 (CD30) protein consists of 595 amino acids and is a type I transmembrane glycoprotein. The structure of TNFRSF8 can be broken down into three key domains:

Extracellular Domain:

• The extracellular region of CD30 contains six cysteine-rich domains (CRDs) that are characteristic of the TNFR superfamily. These domains play a pivotal role in ligand binding and receptor activation. CD30's ligand, known as CD30 ligand (CD30L) or TNFSF8, belongs to the TNF ligand family, and it binds specifically to the extracellular domain of CD30, initiating a cascade of intracellular signaling.
• The CRDs form a scaffold that maintains the receptor in an optimal conformation for ligand interaction. Upon ligand binding, CD30 undergoes conformational changes that lead to the clustering of receptor molecules on the cell surface, facilitating downstream signaling.
• The extracellular domain also contains several N-linked glycosylation sites, which are critical for protein stability, proper folding, and surface expression.

Transmembrane Domain:

• CD30 contains a single transmembrane α-helix consisting of around 21 hydrophobic amino acids that anchor the receptor to the plasma membrane. This domain does not directly participate in signaling but is essential for positioning the extracellular and intracellular domains appropriately for signal transduction.

Cytoplasmic Domain:

• The intracellular tail of CD30 is approximately 200 amino acids long and is responsible for initiating signal transduction once the ligand binds to the extracellular domain. It contains multiple TNFR-associated factor (TRAF) binding motifs, which recruit adaptor proteins such as TRAF2, TRAF5, and TRAF1 upon ligand binding.
• These interactions activate downstream pathways, including the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways. These pathways play crucial roles in cell proliferation, survival, differentiation, and apoptosis.

Classification and Subtypes

CD30 (TNFRSF8) is a member of the tumor necrosis factor receptor superfamily (TNFRSF), which includes receptors that bind to ligands of the TNF superfamily (TNFSF). TNFRSF8 interacts specifically with its ligand CD30 ligand (CD30L), also known as TNFSF8.

The TNFRSF is categorized based on the extracellular cysteine-rich domains (CRDs) and intracellular signaling motifs that allow these receptors to mediate immune and apoptotic responses. CD30 does not have subtypes but interacts with various downstream molecules, especially TRAF proteins, which modulate distinct signaling pathways leading to diverse cellular outcomes.

Function and Biological Significance

CD30 (TNFRSF8) has several vital roles in immune regulation and cellular homeostasis:

T-cell Activation and Differentiation:

• CD30 is expressed transiently on activated CD4+ T cells, CD8+ T cells, and B cells following antigenic stimulation. It is particularly upregulated during Th2-type immune responses. CD30 signaling promotes the proliferation and survival of activated T cells, contributing to the regulation of immune responses.
• In T cells, CD30 promotes effector T cell functions and may modulate the transition between effector and memory T cells, suggesting a role in the maintenance of long-term immune memory.

Regulation of Apoptosis:

• While CD30 signaling primarily promotes cell survival through activation of NF-κB and MAPK pathways, under certain conditions, CD30 can induce apoptosis. The ability to trigger apoptotic signals may depend on the context, such as the strength and duration of CD30L binding, the presence of other co-stimulatory signals, and the balance between pro-survival and pro-apoptotic TRAF proteins.

Role in Immune Responses:

• CD30 signaling modulates the balance between Th1 and Th2 immune responses. Th2 cells, which produce IL-4, IL-5, and IL-13, upregulate CD30 more prominently than Th1 cells, which are involved in cellular immunity. Thus, CD30 plays a role in promoting humoral immunity and allergic responses.
• In B cells, CD30 signaling is less well understood, but it appears to be involved in B cell activation and possibly the formation of plasma cells and germinal centers.

Anti-tumor Immunity:

• CD30 has become a significant target in cancer immunotherapy, especially in lymphomas. CD30-positive lymphomas, such as Hodgkin lymphoma and ALCL, have aberrantly high CD30 expression. Targeting CD30 with monoclonal antibodies, such as brentuximab vedotin, leads to selective killing of CD30-expressing tumor cells through mechanisms like antibody-drug conjugation and antibody-dependent cell-mediated cytotoxicity (ADCC).

Clinical Issues

Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma:

• CD30 is overexpressed in Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma and in anaplastic large cell lymphoma (ALCL). As a surface marker of these malignancies, CD30 serves as both a diagnostic tool and a therapeutic target.
• Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, has shown high efficacy in treating relapsed/refractory Hodgkin lymphoma and ALCL by delivering cytotoxic agents directly to CD30-positive cells.

Autoimmune Diseases:

• CD30 expression has been implicated in various autoimmune diseases. In conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), CD30-expressing T cells accumulate in inflamed tissues, indicating a role for CD30 in the regulation of immune responses in chronic inflammation.
• The exact mechanisms through which CD30 contributes to autoimmune pathology are still under investigation, but it likely involves dysregulation of T-cell activation and a skewing towards Th2-type responses, which can exacerbate autoimmune conditions.

Transplant Rejection:

• Elevated levels of CD30 have been associated with graft-versus-host disease (GVHD) and transplant rejection in patients who undergo solid organ transplantation or hematopoietic stem cell transplantation. Monitoring CD30 expression levels in transplant recipients could serve as a biomarker for immune activation and risk of rejection.

Allergic Diseases:

• Given CD30's association with Th2 responses, which are central to allergic diseases, CD30 signaling is also relevant in conditions such as asthma, eczema, and allergic rhinitis. In these contexts, CD30 promotes the production of Th2 cytokines, which drive allergic inflammation.

Summary

TNFRSF8 (CD30) is a member of the tumor necrosis factor receptor family, playing crucial roles in immune regulation, T-cell activation, and B-cell activation. Structurally, it is composed of an extracellular domain with cysteine-rich repeats, a transmembrane region, and an intracellular tail that recruits TRAF proteins to activate signaling pathways like NF-κB, MAPK, and JNK. These pathways regulate immune responses, including cell survival, differentiation, and apoptosis.

Clinically, CD30 has gained prominence due to its overexpression in Hodgkin lymphoma and ALCL, making it a target for cancer immunotherapy. The development of CD30-targeted therapies, such as brentuximab vedotin, represents a significant advance in treating CD30-positive lymphomas. CD30 is also involved in autoimmune diseases, transplant rejection, and allergic conditions, where it regulates inflammatory and immune responses.

Understanding the multifaceted roles of CD30 in both normal immune function and disease pathogenesis continues to be an important area of research in immunology and oncology.