CD27 - CD27 molecule |Elisa - Clia - Antibody - Protein

Background

CD27, also known as TNFRSF7 (tumor necrosis factor receptor superfamily member 7), is a cell surface receptor primarily expressed on T cells, B cells, and NK cells, playing a pivotal role in the regulation of immune responses. CD27 is a member of the TNF receptor superfamily and functions as a key co-stimulatory molecule, contributing to the development and survival of T lymphocytes, the formation of memory T cells, and the activation of B cells. Its ligand, CD70, also plays an essential role in immune activation, particularly in T-cell-B-cell communication. CD27 engagement through CD70 induces signaling pathways critical for T-cell activation, proliferation, differentiation, and long-term immune memory.

The CD27-CD70 axis is tightly regulated because dysregulation of these pathways can lead to immune system-related diseases, including autoimmune disorders, chronic inflammation, and cancer. In addition to its role in adaptive immunity, CD27 is involved in immune surveillance and the elimination of pathogens and tumor cells. Importantly, CD27 is a target for therapeutic intervention, particularly in immunotherapy strategies aimed at boosting the immune response against cancer.

Protein Structure

The CD27 molecule is a type I transmembrane protein composed of 260 amino acids. Its structure can be divided into several domains, each contributing to its function as a receptor for CD70:

Extracellular Domain:

• The extracellular region of CD27 consists of approximately 185 amino acids, including three cysteine-rich domains (CRDs). These CRDs are characteristic of the TNF receptor superfamily and are crucial for ligand binding. CD27 interacts with its ligand, CD70, through these domains, initiating downstream signaling cascades. The cysteine-rich domains allow the protein to fold into a structure that supports ligand-induced receptor trimerization.
• Glycosylation sites: The extracellular region also contains potential N-linked glycosylation sites, which contribute to protein folding, stability, and the modulation of ligand interactions.

Transmembrane Domain:

• The transmembrane region is composed of 20 hydrophobic amino acids that anchor CD27 in the plasma membrane. This single-pass transmembrane domain allows the extracellular portion to interact with CD70, while the intracellular portion mediates signal transduction.

Intracellular Domain:

• The intracellular tail of CD27 is approximately 35 amino acids long and contains several motifs essential for initiating intracellular signaling. This cytoplasmic region includes TNFR-associated factor (TRAF) binding sites, which are critical for activating downstream signaling pathways like the NF-κB, JNK, and p38 MAPK pathways. These signaling cascades are responsible for cell survival, differentiation, and proliferation, particularly in T cells.

TRAF-binding motifs:

• CD27 recruits members of the TRAF family, particularly TRAF2 and TRAF5, which are essential for its signal transduction. TRAF binding to CD27 leads to the activation of pro-survival and pro-inflammatory pathways, thus enhancing the immune response.

Classification and Subtypes

CD27 belongs to the tumor necrosis factor receptor (TNFR) superfamily, a large group of proteins involved in various aspects of immune regulation, inflammation, and apoptosis. Like other members of this family, CD27 plays a role in co-stimulation, cell survival, and immune system regulation.

While CD27 itself does not have distinct subtypes, its ligand, CD70, is the sole natural ligand for CD27 and belongs to the TNF ligand family. CD27 signaling is highly dependent on its interaction with CD70, which is transiently expressed on activated T and B cells, as well as dendritic cells. The interaction between CD27 and CD70 leads to the formation of a receptor-ligand complex that initiates critical immune signaling pathways.

Function and Biological Significance

CD27 is predominantly expressed on naive T cells, memory T cells, B cells, NK cells, and some dendritic cells. Its primary role is to regulate T-cell immunity, memory formation, and B-cell activation. CD27 performs several key functions:

T-Cell Activation and Differentiation:

• CD27 acts as a co-stimulatory molecule for T cells. Upon activation of T cells through the T-cell receptor (TCR), the interaction of CD27 with CD70 enhances T-cell proliferation and survival, promoting the development of effector T cells and memory T cells. CD27 signaling contributes to the clonal expansion of T cells and plays a role in sustaining T-cell responses during chronic immune challenges.

Memory T Cell Formation:

• CD27 is critical for the formation of memory T cells, which are essential for long-term immunity and rapid responses to previously encountered pathogens. CD27 signaling supports the survival and maintenance of central memory T cells, which reside in lymphoid organs and can rapidly differentiate into effector cells upon re-exposure to antigen.

B-Cell Activation and Antibody Production:

• In B cells, CD27 functions as a marker for memory B cells and is involved in promoting immunoglobulin production. CD27 signaling enhances B-cell differentiation into plasma cells, which produce antibodies necessary for the humoral immune response. CD27 expression on B cells also plays a role in maintaining the longevity of memory B cells.

Regulation of Apoptosis:

• CD27 has a pro-survival role but can also mediate apoptotic signals under certain conditions. The balance between survival and death signaling is influenced by the intensity and duration of CD27-CD70 interactions, as well as the cellular context. CD27-mediated apoptosis is important for maintaining immune homeostasis by eliminating over-activated or dysfunctional T cells.

NK Cell Function:

• CD27 is expressed on a subset of NK cells and contributes to NK cell activation. CD27 signaling enhances NK cell-mediated cytotoxicity against tumor cells and virally infected cells, making it important in immune surveillance.

Immune Surveillance and Tumor Immunity:

• CD27 is involved in immune surveillance, particularly in recognizing and eliminating tumor cells. Its interaction with CD70 on dendritic cells and other antigen-presenting cells (APCs) promotes T-cell activation against cancer cells, making CD27 a potential target for cancer immunotherapy.

Clinical Issues

Cancer:

• CD27 plays a role in tumor immunity by promoting T-cell activation and memory formation. However, some tumors, particularly lymphomas, can exploit the CD27-CD70 axis to evade immune surveillance. CD70 overexpression in tumors can lead to chronic CD27 signaling, which may suppress effective anti-tumor immunity. CD27-targeting therapies, including agonistic antibodies and CD27-based immunotherapies, are being investigated in clinical trials for their potential to enhance anti-tumor responses by promoting T-cell and NK cell activation.

Autoimmune Disorders:

• Dysregulation of the CD27-CD70 pathway has been implicated in various autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Chronic stimulation of CD27 by CD70 can lead to excessive immune activation, contributing to the development of autoimmune pathology. Inhibiting the CD27-CD70 interaction may be a therapeutic strategy for mitigating overactive immune responses in autoimmune conditions.

Infectious Diseases:

• CD27 is crucial for the formation of long-term memory T cells that are essential for immunity against recurrent infections. In viral infections such as HIV, CD27 expression is downregulated on exhausted T cells, which impairs the immune response. Understanding how to modulate CD27 signaling in the context of chronic infections could improve therapeutic strategies for enhancing immune resilience.

Immunodeficiencies:

• CD27 deficiencies or mutations can lead to primary immunodeficiency disorders characterized by impaired T-cell function and susceptibility to infections. Patients with CD27 deficiency often exhibit persistent viral infections, particularly with Epstein-Barr virus (EBV), and are at increased risk for lymphoproliferative disorders. CD27 deficiency underscores the importance of this molecule in regulating immune function and maintaining T-cell memory.

Summary

The CD27 molecule is a critical member of the TNF receptor superfamily involved in the regulation of T-cell activation, memory formation, and immune responses. Its role as a co-stimulatory receptor on T cells, B cells, and NK cells allows it to enhance immune responses during infections, cancer, and autoimmune diseases. The CD27-CD70 interaction drives the proliferation and differentiation of immune cells, promoting the formation of long-lasting memory T and B cells that are essential for durable immunity. However, dysregulation of this pathway is associated with cancer, autoimmune diseases, and chronic infections, highlighting its clinical significance.

CD27 is a target for therapeutic intervention in cancer immunotherapy, where enhancing its signaling can boost anti-tumor immunity. Conversely, inhibiting CD27 signaling in autoimmune disorders may alleviate excessive immune responses. CD27’s critical involvement in immune homeostasis and its clinical relevance make it a key molecule of interest in immunology and therapeutic development.