TNFSF8 - TNF superfamily member 8 |Elisa - Clia - Antibody - Protein

Background

Tumor necrosis factor superfamily member 8 (TNFSF8), also known as CD30 ligand (CD30L) or CD153, is a cell surface molecule encoded by the TNFSF8 gene located on chromosome 9 in humans. This protein is part of the tumor necrosis factor (TNF) superfamily, a group of proteins that are involved in the regulation of immune responses, cell survival, proliferation, differentiation, and apoptosis. TNFSF8 is primarily expressed on the surface of activated T cells, B cells, and certain myeloid cells. Its main receptor is CD30, a member of the TNF receptor superfamily, commonly expressed on activated T and B cells, particularly in the context of immune responses, as well as in certain cancers. TNFSF8/CD30L-CD30 signaling plays a pivotal role in T-cell and B-cell interactions, modulating immune responses that are critical for defending against pathogens and maintaining immune homeostasis.

The TNFSF8-CD30 axis is increasingly recognized for its contributions to immune regulation, particularly in conditions involving chronic inflammation and autoimmune disorders. Additionally, the TNFSF8 pathway has been implicated in cancer biology, where it supports the growth of certain lymphoma subtypes, including Hodgkin’s lymphoma and certain non-Hodgkin lymphomas. Because of these roles, TNFSF8 is a focus of therapeutic interest, especially in the development of immune-modulating agents.

Protein Structure

TNFSF8 is a type II transmembrane protein with a molecular weight of approximately 26-30 kDa. It is synthesized as a precursor protein that undergoes post-translational modifications to form a mature, active protein. Structurally, TNFSF8 can be characterized by the following domains:

Extracellular Domain (ECD):

• The extracellular domain is responsible for binding to CD30, its receptor on target cells. This region consists of approximately 150 amino acids and includes a TNF homology domain, which is characteristic of the TNF superfamily. This domain is crucial for receptor binding and the initiation of downstream signaling pathways.
• The TNF homology domain adopts a typical “jelly-roll” beta-sandwich fold, which is involved in ligand-receptor interactions and is conserved among TNF superfamily members.
• TNFSF8 can exist in both membrane-bound and soluble forms, with the latter produced via proteolytic cleavage. Both forms are capable of binding CD30, although they may have different biological effects.

Transmembrane Domain (TMD):

• TNFSF8 has a single transmembrane helix that anchors it within the cellular membrane, contributing to its role as a membrane-bound ligand.
• This domain plays a structural role, ensuring the correct orientation and stability of the protein within the membrane. The transmembrane nature is essential for the molecule’s function as a membrane-bound cytokine, although soluble forms retain partial activity.

Cytoplasmic Domain (CD):

• The cytoplasmic tail of TNFSF8 is relatively short and does not contain well-defined signaling motifs, as TNFSF8 primarily functions by interacting with CD30 rather than signaling directly.
• However, the cytoplasmic region is important for intracellular trafficking and may influence the rate of TNFSF8 presentation on the cell surface.

Classification and Subtypes

TNFSF8 belongs to the TNF superfamily, which consists of cytokines that can induce various cellular responses, from proliferation and differentiation to apoptosis. TNFSF8 does not have distinct subtypes but exists in different forms, primarily membrane-bound and soluble. These forms result from proteolytic cleavage and have overlapping yet distinct functions. The TNF superfamily has several related ligands, including TNFSF4 (OX40L), TNFSF5 (CD40L), and TNFSF14 (LIGHT), but TNFSF8 specifically interacts with CD30, its sole receptor.

Function and Biological Significance

The biological functions of TNFSF8 stem from its interactions with CD30 on immune cells, impacting immune cell activation, differentiation, and survival.

Regulation of Immune Responses:

• TNFSF8-CD30 interactions play an important role in modulating T cell responses. CD30 signaling can promote the activation and proliferation of T cells, particularly T helper 2 (Th2) cells, which are essential for humoral immune responses.
• The TNFSF8-CD30 pathway also modulates T cell and B cell interactions, enhancing B cell activation, antibody production, and isotype switching, contributing to the adaptive immune response.

Role in Inflammation and Autoimmunity:

• TNFSF8 is highly expressed in activated lymphocytes during chronic inflammation. This ligand-receptor pair can amplify immune responses in inflamed tissues, with studies suggesting that dysregulation of TNFSF8-CD30 signaling contributes to autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
• In autoimmunity, TNFSF8-CD30 signaling promotes the survival of autoreactive T cells, perpetuating inflammatory responses.

Cancer Biology:

• TNFSF8-CD30 signaling is involved in the pathogenesis of several cancers, particularly Hodgkin lymphoma and certain non-Hodgkin lymphomas. The signaling pathway supports the growth and survival of malignant cells in these cancers.
• Elevated TNFSF8 expression has also been observed in various solid tumors, where it may contribute to tumor-associated immune evasion mechanisms. Targeting TNFSF8 or CD30 in such cancers is being explored as a therapeutic approach.

Apoptotic Signaling:

• In addition to promoting cell survival, TNFSF8-CD30 signaling can also lead to apoptosis under certain conditions. This dual functionality is context-dependent and influenced by the levels of TNFSF8 expression, the state of the target cell, and the presence of other cytokines.

Clinical Issues

Given its roles in immune regulation and cancer, TNFSF8 is associated with a range of clinical conditions:

Autoimmune Diseases:

• Dysregulation of TNFSF8 has been observed in autoimmune diseases like rheumatoid arthritis, where it contributes to the persistence of inflammation and tissue damage. Targeting TNFSF8 or its receptor CD30 may have therapeutic potential for modulating immune responses in these conditions.

Lymphomas:

• The TNFSF8-CD30 signaling pathway is a therapeutic target in CD30-positive lymphomas, including Hodgkin lymphoma and certain T cell lymphomas. Monoclonal antibodies and antibody-drug conjugates (ADCs) targeting CD30, such as brentuximab vedotin, have shown clinical efficacy in these cancers by delivering cytotoxic agents directly to CD30-expressing tumor cells.

Immunodeficiency Disorders:

• Individuals with mutations in the TNFSF8 gene or CD30 may experience immunodeficiency characterized by inadequate T and B cell interactions, resulting in compromised antibody responses and increased susceptibility to infections.

Allergic and Asthmatic Conditions:

• Elevated TNFSF8-CD30 signaling has been implicated in promoting Th2-dominated immune responses, characteristic of allergic and asthmatic conditions. Therapeutic interventions that modulate this pathway could have implications in managing chronic allergic inflammation.

Summary

TNFSF8, or CD30 ligand, is a member of the TNF superfamily, playing a crucial role in immune regulation, T and B cell interactions, and inflammatory responses. Structurally, TNFSF8 is a transmembrane protein featuring an extracellular TNF homology domain, a transmembrane domain, and a short cytoplasmic tail. It binds exclusively to CD30, a receptor primarily expressed on activated lymphocytes, transmitting signals that influence cell proliferation, survival, and apoptosis. TNFSF8 is involved in various physiological processes, including immune modulation and inflammatory response regulation, but dysregulation of TNFSF8-CD30 signaling is implicated in autoimmune diseases, cancers, and immunodeficiencies. Consequently, the TNFSF8-CD30 axis is an attractive target in oncology, with treatments aimed at blocking this pathway showing efficacy in CD30-positive lymphomas. As a regulator of inflammation, immunity, and cell survival, TNFSF8 remains a key molecule of interest in therapeutic development across a range of immune and inflammatory diseases.