CD209 - CD209 molecule |Elisa - Clia - Antibody - Protein

Background

CD209, commonly known as DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin), is a type II transmembrane protein receptor primarily expressed on the surface of dendritic cells (DCs) and some macrophage subsets. It plays a crucial role in the immune system by mediating pathogen recognition, cellular adhesion, and antigen capture. CD209 is a member of the C-type lectin receptor (CLR) family and exhibits high affinity for mannose-rich glycans, a feature that enables it to bind to a range of microbial structures, facilitating the immune response against pathogens.

One of CD209's defining characteristics is its ability to recognize pathogen-associated molecular patterns (PAMPs), which are specific carbohydrate patterns on pathogens. By binding to these patterns, CD209 captures and internalizes pathogens, aiding in their processing and subsequent antigen presentation to T cells. The receptor is particularly relevant in the context of HIV, Mycobacterium tuberculosis, Ebola, and Dengue virus, as it can interact with these pathogens and contribute to their immune response or facilitate viral entry in certain cases.

Protein Structure

The structure of CD209 is tailored to support its role in pathogen binding, immune cell adhesion, and endocytosis. CD209 is a type II transmembrane receptor with the following structural organization:

1. Extracellular Domain: The extracellular domain of CD209 contains two key regions:

• C-type Lectin-like Domain (CTLD): This is the primary ligand-binding domain, located at the C-terminal end of the receptor. The CTLD is responsible for the calcium-dependent binding to mannose-rich glycans, a characteristic that enables CD209 to recognize a variety of pathogen surfaces. This domain also includes the carbohydrate recognition domain (CRD), which is finely tuned to bind high-mannose oligosaccharides. The specific structural arrangement within the CRD allows CD209 to distinguish pathogen-associated glycans from host glycans, providing a mechanism for targeted immune recognition.
• Neck Region: Adjacent to the CTLD, CD209 has a flexible neck region containing multiple tandem repeats. This neck domain enhances the spatial arrangement of the CRD, allowing multivalent binding to pathogens. The length and flexibility of this neck region enable CD209 to reach and bind to ligands on cell surfaces or viral particles at variable distances, facilitating clustering and enhancing the receptor’s ability to capture larger pathogens or multiple particles simultaneously.

1. Transmembrane Domain: The transmembrane domain of CD209 anchors the receptor to the plasma membrane. This positioning enables CD209 to reach into the extracellular space to capture pathogens, while simultaneously linking it to the cellular signaling pathways in dendritic cells.
2. Cytoplasmic Tail: The cytoplasmic tail of CD209 contains sorting signals and motifs necessary for internalization of the receptor-ligand complex. The tail is involved in clathrin-mediated endocytosis and includes a tyrosine-based motif, which is essential for internalizing bound pathogens. This process enables dendritic cells to transport captured pathogens into endosomes, where they can be processed and presented on major histocompatibility complex (MHC) molecules for adaptive immune responses.

Overall, the structural organization of CD209, with its extracellular C-type lectin domain, flexible neck region, and efficient endocytic signaling motifs, supports its function in pathogen recognition, cellular adhesion, and antigen processing.

Classification and Subtypes

CD209 is part of the C-type lectin receptor (CLR) family, specifically in the Group II CLRs, which are defined by their role in immune cell function, particularly in pathogen recognition and antigen presentation. Within this group, CD209 is closely related to other dendritic cell-specific receptors like CD207 (langerin) but is unique in its expression profile and specific ligand affinities.

While CD209 itself does not have defined subtypes or isoforms with significantly different functions, variations in its expression are observed on different dendritic cell subsets and macrophages, particularly in response to inflammatory stimuli. Related receptors within the same lectin family, such as DC-SIGNR (CD209L), share structural and functional similarities but are typically found on endothelial cells rather than dendritic cells and have subtle differences in their binding affinities and immune roles.

Function and Biological Significance

CD209 serves multiple essential functions within the immune system:

1. Pathogen Recognition and Binding: CD209’s high affinity for mannose-rich glycans allows it to recognize and bind a variety of pathogens, including viruses (HIV, Ebola, Dengue), bacteria (Mycobacterium tuberculosis, Helicobacter pylori), and fungi (Candida albicans). Upon binding, CD209 facilitates pathogen uptake and endocytosis, directing the pathogen to intracellular compartments for antigen processing.
2. Antigen Presentation and T-cell Activation: After pathogen uptake, CD209 directs internalized pathogens to endosomal and lysosomal compartments, where they undergo degradation into antigenic peptides. These peptides are then presented on MHC class II molecules to CD4+ T cells, a process critical for initiating adaptive immunity. By enabling pathogen capture and facilitating antigen processing, CD209 on dendritic cells bridges the innate and adaptive immune responses.
3. Cellular Adhesion and Immunological Synapse Formation: CD209 interacts with adhesion molecules, such as ICAM-3, on T cells, facilitating the formation of the immunological synapse. This synapse is essential for effective communication between dendritic cells and T cells, supporting T-cell priming and activation. This adhesion function also allows dendritic cells to interact with other cells in the lymphoid tissue, coordinating the immune response.
4. Immune Modulation and Inflammatory Responses: Through its signaling pathways, CD209 modulates inflammatory responses and can influence cytokine production. By binding to pathogen-specific ligands, CD209 activation can lead to the release of pro-inflammatory cytokines that enhance the immune response. However, certain pathogens exploit CD209-mediated signaling to subvert the immune system, which has implications for pathogen survival and persistence.
5. Role in Viral Transmission and Immune Evasion: Some viruses, notably HIV, exploit CD209 to gain entry into dendritic cells and other host cells. By binding to CD209, HIV can be internalized by dendritic cells and potentially spread to T cells, facilitating viral transmission within the host. This interaction illustrates how pathogens can manipulate CD209 to evade immune detection, highlighting the complex role of CD209 in both defense and disease.

Clinical Issues

The involvement of CD209 in pathogen recognition and immune modulation has implications in various infectious and inflammatory diseases:

1. HIV and Viral Infections: CD209’s interaction with HIV is well-documented, as the receptor facilitates viral binding and uptake. This interaction is significant in HIV transmission because dendritic cells, via CD209, can capture HIV and potentially transfer the virus to T cells, enhancing viral spread. Targeting CD209’s interaction with HIV is an area of therapeutic interest, as blocking this binding could reduce viral entry and transmission.
2. Tuberculosis: In tuberculosis, Mycobacterium tuberculosis binds to CD209 on macrophages and dendritic cells, allowing the bacteria to evade immune responses. This interaction enhances bacterial survival and persistence in the host. Therapeutic strategies to disrupt CD209-Mycobacterium interactions may improve host resistance to tuberculosis.
3. Immune Evasion by Pathogens: Several other pathogens, including Ebola and Dengue viruses, exploit CD209 to enter and evade immune cells. These pathogens use CD209 as a “Trojan horse” to gain access to dendritic cells, facilitating their survival and spread. Blocking CD209 interactions with these pathogens could help to prevent infections and improve outcomes in diseases caused by these organisms.
4. Inflammatory Diseases and Autoimmunity: Aberrant expression of CD209 is associated with autoimmune and chronic inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE). Elevated CD209 expression on dendritic cells in inflamed tissues contributes to chronic inflammation by enhancing immune cell recruitment and cytokine production. Modulating CD209 expression or function could help reduce inflammation and prevent tissue damage in autoimmune conditions.
5. Cancer: CD209’s role in antigen capture and presentation also has implications for cancer immunotherapy. By targeting tumor antigens to CD209-expressing dendritic cells, researchers aim to boost anti-tumor immune responses. Additionally, the receptor’s expression in the tumor microenvironment, especially in tumor-associated dendritic cells, may influence immune cell infiltration and tumor progression.

Summary

CD209, or DC-SIGN, is a type II transmembrane receptor that is highly expressed on dendritic cells and some macrophages, where it plays an integral role in immune recognition, pathogen capture, and antigen presentation. Structurally, CD209 is characterized by its C-type lectin-like domain and a flexible neck region that enhances its ability to capture pathogens, including viruses, bacteria, and fungi, via their mannose-rich glycans. The receptor’s cytoplasmic tail supports internalization of pathogens, directing them for antigen processing and T cell presentation, which is essential for adaptive immunity.

Clinically, CD209’s role in pathogen recognition is significant in infections, such as HIV and tuberculosis, where pathogens exploit the receptor to enter and evade immune responses. Inflammatory diseases and autoimmune disorders have also been associated with altered CD209 expression, contributing to chronic inflammation and tissue damage. Additionally, its potential role in cancer immunotherapy presents a novel approach to targeting CD209 in dendritic cells to enhance anti-tumor responses.

In summary, CD209 is a critical receptor in the immune system, balancing its roles in immune activation and pathogen recognition with challenges in pathogen exploitation and immune evasion. Therapeutic targeting of CD209 may help to manage infectious, inflammatory, and neoplastic diseases, positioning it as an important receptor in immunology and therapeutic research.