CD70 - CD70 molecule |Elisa - Clia - Antibody - Protein

Background

CD70, also known as TNFSF7 (Tumor Necrosis Factor Superfamily Member 7), is a transmembrane glycoprotein that belongs to the tumor necrosis factor (TNF) ligand superfamily. It is primarily expressed on the surface of activated immune cells, including T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. The expression of CD70 is tightly regulated and is typically transient, occurring upon immune cell activation, particularly during the adaptive immune response. CD70 plays a crucial role in immune cell interactions, contributing to T cell proliferation, differentiation, and the development of memory T cells.

CD70 exerts its effects by binding to its receptor, CD27, which is a member of the TNF receptor superfamily. CD27 is constitutively expressed on naïve T cells, memory T cells, and NK cells, and its interaction with CD70 initiates intracellular signaling pathways that enhance immune activation and memory formation. This CD70-CD27 interaction is critical for effective immune responses, particularly during viral infections, tumor immunity, and in the context of autoimmune diseases.

Given its role in immune cell activation, CD70 is implicated in a variety of diseases, including autoimmune disorders, chronic infections, and cancers. In these conditions, dysregulation of CD70 expression or signaling can lead to either hyperactivation of immune cells or immune evasion by tumor cells. Therapeutically, CD70 is being explored as a target for cancer immunotherapy and for treatments aimed at controlling excessive immune responses.

Protein Structure

CD70 is a type II transmembrane protein, meaning it has an extracellular domain that interacts with its receptor, CD27, and a cytoplasmic tail that anchors it within the plasma membrane. The structure of CD70 can be characterized by the following key features:

Extracellular Domain:

• The extracellular portion of CD70 contains a TNF homology domain, which is typical of proteins in the TNF ligand superfamily. This domain facilitates the binding of CD70 to its receptor, CD27. Upon binding, CD70 initiates receptor oligomerization and subsequent signaling pathways within the target cell.
• The TNF homology domain is also responsible for mediating trimerization of CD70, which is required for efficient receptor activation. CD70 typically exists as a trimer on the cell surface, and this oligomerization is critical for its functional activity.

Transmembrane Domain:

• CD70 is anchored in the plasma membrane via a single transmembrane helix. This region spans the lipid bilayer and stabilizes the protein on the cell surface, allowing its extracellular domain to interact with CD27 on neighboring cells.

Cytoplasmic Tail:

• The cytoplasmic tail of CD70 is relatively short but contains sequences necessary for intracellular trafficking and regulation of its surface expression. This region is also involved in interactions with other intracellular proteins that modulate the protein’s stability and recycling between the cell surface and internal compartments.

Disulfide Bonds and Glycosylation:

• CD70 is stabilized by disulfide bonds within its extracellular domain, which maintain the correct folding and structural integrity of the protein. Additionally, it undergoes N-linked glycosylation, which may influence its stability and interactions with CD27. Glycosylation can also affect the protein’s localization and half-life on the cell surface.

Trimerization:

• Like other TNF ligands, CD70 forms homotrimers that are essential for its biological activity. This trimeric structure is critical for cross-linking and activating the CD27 receptor on target cells, thereby initiating downstream signaling cascades.

Classification and Subtypes

CD70 belongs to the tumor necrosis factor ligand superfamily (TNFSF), which is composed of proteins that typically function as membrane-bound cytokines involved in regulating immune cell survival, activation, and apoptosis. Specifically, CD70 is part of the TNFSF7 subgroup, which includes ligands that interact with receptors in the TNF receptor superfamily (TNFRSF).

CD70 does not have well-defined subtypes. However, variations in CD70 expression patterns and post-translational modifications may occur in different cell types or under specific physiological and pathological conditions. While CD70 expression is typically transient and restricted to activated immune cells, it can be aberrantly expressed in some cancers, making it a potential therapeutic target in oncology.

Function and Biological Significance

CD70 plays a pivotal role in the regulation of immune responses, particularly through its interaction with CD27. The CD70-CD27 axis has several key biological functions:

T Cell Activation and Proliferation:

• Upon T cell activation, CD70 is upregulated and engages CD27 on the surface of naïve and memory T cells. This interaction provides co-stimulatory signals that are essential for full T cell activation, promoting T cell proliferation, survival, and cytokine production. CD70-CD27 signaling also enhances the differentiation of effector T cells, which are crucial for the clearance of pathogens and tumors.

Memory T Cell Development:

• CD70-CD27 signaling is essential for the formation and maintenance of memory T cells, which are responsible for rapid and robust immune responses upon re-exposure to pathogens. Mice deficient in CD27 or CD70 show impaired memory T cell responses, highlighting the importance of this pathway in adaptive immunity.

NK Cell Function:

• CD70 expression on dendritic cells and other antigen-presenting cells (APCs) also enhances the activation and cytotoxic function of NK cells through CD27 engagement. This promotes the ability of NK cells to kill infected or malignant cells, contributing to innate immune defense.

B Cell Responses:

• In addition to its effects on T cells, CD70 also influences B cell responses. CD70-CD27 signaling enhances B cell activation and antibody production, particularly during the formation of germinal centers in lymphoid tissues. This promotes long-lasting humoral immunity.

Immune Regulation in Cancer:

• CD70 expression has been detected in various cancers, including renal cell carcinoma, glioblastoma, and lymphomas. In the tumor microenvironment, CD70 can either promote anti-tumor immunity by stimulating T cells or contribute to immune evasion by promoting the expansion of regulatory T cells (Tregs), which suppress anti-tumor immune responses. Targeting the CD70-CD27 pathway is currently under investigation as a strategy to boost tumor immunotherapy.

Clinical Issues

Autoimmune Diseases:

• Aberrant CD70 expression or dysregulated CD27 signaling can contribute to the pathogenesis of autoimmune diseases. Overactivation of the CD70-CD27 pathway may lead to excessive T cell activation and chronic inflammation, which are hallmarks of conditions such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA). Therapeutic strategies targeting CD70-CD27 interactions may help mitigate the immune hyperactivity in these diseases.

Cancer:

• CD70 is often overexpressed in solid tumors and hematologic malignancies, such as renal cell carcinoma, glioblastoma, and Hodgkin's lymphoma. In these cancers, CD70 expression correlates with poor prognosis, as it can promote immune suppression by expanding regulatory T cells and creating a more immunosuppressive tumor microenvironment. As a result, CD70 has become an attractive target for cancer immunotherapy. Antibody-drug conjugates (ADCs) targeting CD70, as well as CD70-specific chimeric antigen receptor (CAR)-T cell therapies, are under development to treat CD70-expressing tumors.

Chronic Infections:

• In the context of chronic infections, such as HIV or hepatitis, persistent expression of CD70 on immune cells may contribute to immune exhaustion. CD70-CD27 interactions may drive the continual activation of T cells, leading to their dysfunction and failure to control the infection. Modulating this pathway could improve immune responses in chronic infection settings.

Transplantation:

• CD70 is also relevant in organ transplantation, where its expression on immune cells may influence graft rejection. Blocking CD70-CD27 signaling could help prevent the activation of alloreactive T cells, reducing the likelihood of transplant rejection.

Summary

CD70 is a transmembrane glycoprotein that belongs to the tumor necrosis factor ligand superfamily. It is transiently expressed on activated immune cells, including T cells, B cells, dendritic cells, and NK cells. CD70 functions primarily through its interaction with its receptor, CD27, which is involved in regulating T cell activation, memory T cell development, and NK cell function. Structurally, CD70 features an extracellular TNF homology domain, a transmembrane region, and a cytoplasmic tail, and it forms functional trimers that activate CD27.

The biological significance of CD70 lies in its role in immune regulation, including promoting effective responses to pathogens and tumors. However, dysregulation of CD70 expression is implicated in several clinical conditions, including autoimmune diseases, cancers, and chronic infections. CD70 is emerging as a target for cancer immunotherapy, with therapeutic approaches aimed at modulating its activity to boost anti-tumor immunity.