CLEC9A - C-type lectin domain containing 9A |Elisa - Clia - Antibody - Protein

Background

CLEC9A, also known as C-type lectin domain family 9 member A or DNGR-1 (Dendritic Cell Natural Killer Lectin Group Receptor 1), is an immune receptor primarily expressed on a subset of dendritic cells (DCs) and certain populations of macrophages. CLEC9A is part of the C-type lectin receptor (CLR) family, which is known for its role in recognizing carbohydrate structures on pathogens, triggering immune responses, and presenting antigens to T cells. However, CLEC9A is unique within this family for its specialized function in detecting necrotic cells and facilitating the cross-presentation of antigens from dead cells. This capability enables CLEC9A to bridge innate and adaptive immunity, playing a significant role in immune responses to infections, cancer, and tissue injury.

The receptor's ability to recognize damaged cells, rather than simply pathogens, underscores its importance in contexts such as infection, cancer immunology, and autoimmunity. CLEC9A has therefore gained interest for its potential applications in vaccine development and immunotherapy. Its expression is mainly restricted to CD8+ DCs and their human equivalent, BDCA3+ DCs, which are specialized for cross-presentation, making CLEC9A a critical component in inducing CD8+ T cell responses.

Protein Structure

CLEC9A’s structure is integral to its ability to recognize ligands associated with necrotic cells and to initiate intracellular signaling:

Extracellular C-type Lectin-like Domain (CTLD):

• CLEC9A possesses a C-type lectin-like domain, which is structurally related to other members of the CLR family but exhibits unique features that allow it to bind ligands associated with necrotic cells. Unlike classical C-type lectins, which typically require calcium ions for carbohydrate binding, CLEC9A binds ligands independently of calcium. Its CTLD does not engage in typical carbohydrate recognition; instead, it detects exposed actin filaments on damaged or necrotic cells.
• The CTLD has a highly conserved binding groove that is selective for actin complexes and other intracellular components that become exposed upon cell damage, making it well-suited for detecting cellular debris from necrotic cells rather than intact pathogens.

Stalk Region:

• The stalk region of CLEC9A provides structural support and flexibility to the CTLD, allowing it to engage with ligands on the surfaces of necrotic cells. This flexibility enables the receptor to interact efficiently with various cell fragments, improving its recognition capabilities.

Transmembrane Domain:

• CLEC9A contains a single-pass transmembrane domain that anchors the protein to the cell membrane. This anchoring allows the extracellular CTLD to access ligands on necrotic cells while situating the intracellular signaling domains for downstream activation.

Cytoplasmic Tail with Immunoreceptor Tyrosine-based Activation Motif (ITAM)-like Domain:

• CLEC9A has a cytoplasmic tail containing an ITAM-like motif. This motif, upon ligand engagement, undergoes phosphorylation and recruits Syk family kinases, which initiate signaling cascades that lead to cellular activation and cytokine production.
• The ITAM-like domain is essential for signal transduction following CLEC9A-ligand interaction, promoting endocytosis and subsequent antigen processing and presentation.

Classification and Subtypes

CLEC9A is classified within the C-type lectin receptor family, specifically within a subgroup of CLRs that recognize cellular damage and aid in antigen presentation. While CLEC9A does not have major subtypes, it is closely related to other CLRs that interact with damaged cells or necrotic tissue, such as CLEC7A (Dectin-1) and CLEC4A (Dendritic Cell Immunoreceptor, DCIR), which also play roles in sensing cell damage or microbial components. CLEC9A’s expression on specialized dendritic cells (CD8+ DCs and BDCA3+ DCs) gives it a unique role in antigen cross-presentation, setting it apart from other CLRs with broader distribution patterns.

Function and Biological Significance

CLEC9A has several key functions, primarily in linking the detection of necrotic cells with the induction of adaptive immune responses:

Detection of Necrotic Cells:

• CLEC9A detects actin filaments and other intracellular components that become exposed on necrotic cells. This recognition allows CLEC9A-expressing dendritic cells to identify and respond to damaged cells within tissues, which is crucial in various pathological contexts, including infection, trauma, and cancer.
• Unlike pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs), CLEC9A responds to damage-associated molecular patterns (DAMPs) from host cells, a unique capability within the CLR family.

Cross-Presentation of Antigens:

• One of CLEC9A’s most significant roles is facilitating the cross-presentation of antigens from necrotic cells to CD8+ T cells. Upon ligand binding, CLEC9A internalizes necrotic cell fragments and processes them for antigen presentation on MHC class I molecules. This process is essential for generating cytotoxic T cell responses against pathogens or tumor cells, as it enables dendritic cells to present antigens from non-viable cells that would otherwise not be detected by the immune system.
• This capability is critical for initiating immune responses to certain viruses, tumors, and intracellular bacteria, which may otherwise evade detection by infecting or residing within host cells.

Promotion of Cytokine Production and Immune Activation:

• Through its ITAM-like domain, CLEC9A activates Syk-dependent signaling pathways, leading to the production of pro-inflammatory cytokines that recruit and activate other immune cells. This enhances the immune response in regions with tissue damage or necrosis, aiding in pathogen clearance or the targeting of tumor cells.
• CLEC9A activation also supports the maturation and activation of dendritic cells, enhancing their ability to stimulate T cells and coordinate adaptive immune responses.

Role in Cancer Immunity:

• CLEC9A’s role in antigen cross-presentation makes it significant in cancer immunity. By enabling dendritic cells to present tumor-associated antigens from necrotic tumor cells, CLEC9A facilitates the activation of CD8+ T cells that can target and destroy cancer cells. This function has made CLEC9A a target of interest in cancer immunotherapy, as enhancing CLEC9A-mediated cross-presentation could improve the efficacy of anti-tumor immune responses.

Clinical Issues

Cancer and Immunotherapy:

• Due to its role in antigen cross-presentation, CLEC9A is being investigated as a target in cancer immunotherapy. Targeting CLEC9A on dendritic cells may improve the presentation of tumor antigens to CD8+ T cells, boosting anti-tumor immunity. Strategies to enhance CLEC9A function, such as using CLEC9A-targeted vaccines or agonistic antibodies, are under investigation in preclinical and clinical studies.
• There is interest in developing CLEC9A-based adjuvants for cancer vaccines, as stimulating CLEC9A could enhance the immune response to tumor-associated antigens.

Autoimmunity and Inflammatory Diseases:

• CLEC9A’s role in recognizing necrotic cells and promoting inflammatory responses raises the potential for involvement in autoimmune diseases, where an inappropriate response to cellular debris could trigger chronic inflammation. Overactive CLEC9A signaling could contribute to autoimmune pathologies by maintaining an inflammatory environment in tissues, perpetuating tissue damage.
• Therapeutic targeting of CLEC9A in autoimmune diseases is still under investigation, but approaches that modulate CLEC9A activity could potentially alleviate symptoms in conditions driven by excessive tissue damage and inflammation.

Infectious Diseases:

• CLEC9A’s ability to detect necrotic cells and promote antigen cross-presentation is beneficial in infectious diseases where cell death is common, such as viral or intracellular bacterial infections. However, some pathogens may exploit CLEC9A pathways to evade immunity by inducing apoptosis or necrosis in host cells to create an immune-privileged environment.
• Understanding how CLEC9A responds to infections and developing strategies to enhance its function could be valuable in combating infectious diseases that lead to high rates of cell death.

Summary

CLEC9A, or DNGR-1, is a C-type lectin receptor that plays a specialized role in detecting necrotic cells and facilitating antigen cross-presentation on dendritic cells. Its structure, featuring a C-type lectin-like domain adapted for binding actin and other necrotic cell markers, and an ITAM-like cytoplasmic tail for initiating immune signaling, makes CLEC9A highly effective in bridging innate and adaptive immunity. CLEC9A’s selective expression on CD8+ DCs (in mice) and BDCA3+ DCs (in humans) positions it as a key receptor in presenting antigens from damaged cells to CD8+ T cells, thus playing a central role in anti-tumor immunity and responses to intracellular pathogens.

Clinically, CLEC9A is a promising target in cancer immunotherapy and vaccine development, as its activation enhances the immune response to tumor antigens and may improve vaccine efficacy. Its role in inflammation also suggests potential implications in autoimmunity, where excessive responses to tissue damage could exacerbate disease. CLEC9A remains a focus of research in immunology and therapeutic development due to its unique role in sensing necrosis and presenting antigens to drive effective CD8+ T cell responses.