CLEC4C - C-type lectin domain family 4 member C |Elisa - Clia - Antibody - Protein

Background

CLEC4C, also known as CD303 or BDCA-2 (Blood Dendritic Cell Antigen 2), is a member of the C-type lectin domain family 4 of receptors and is highly specific to plasmacytoid dendritic cells (pDCs), a subset of immune cells that are crucial for antiviral responses. CLEC4C serves as a pattern recognition receptor (PRR), identifying and binding to carbohydrate structures on pathogens, which helps initiate immune responses. Unlike many other C-type lectins that are broadly expressed on various immune cells, CLEC4C is primarily expressed on pDCs, a unique cell type specializing in the secretion of large quantities of type I interferons (IFN-α/β) in response to viral infections. This exclusive expression gives CLEC4C a unique role in the immune system, particularly in antiviral defense and modulating immune responses in both innate and adaptive immunity.

CLEC4C is involved in immune modulation by inhibiting type I interferon production when cross-linked, adding another layer to immune regulation. It is studied extensively in the context of autoimmune diseases and chronic infections because of its involvement in pDC-mediated responses. Furthermore, its specific expression on pDCs has made CLEC4C a target for therapeutic interventions aimed at modulating pDC activity in autoimmune diseases and certain cancers.

Protein Structure

CLEC4C is a type II transmembrane protein with a single-pass transmembrane domain and an extracellular C-type lectin-like domain (CTLD). Its structural characteristics are integral to its function as a receptor on plasmacytoid dendritic cells.

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

• The extracellular portion of CLEC4C contains the C-type lectin-like domain (CTLD), which is characteristic of C-type lectin receptors (CLRs). This domain facilitates the recognition and binding of carbohydrate molecules, specifically those with terminal mannose or fucose residues. CLEC4C’s CTLD does not require calcium for carbohydrate binding, differing from many other C-type lectins that are calcium-dependent.
• Structural analysis of the CTLD reveals a binding pocket that interacts with glycan structures, suggesting that CLEC4C recognizes carbohydrate moieties on pathogens or glycosylated ligands. However, CLEC4C’s exact binding specificity is less characterized than other lectins in its family, which may indicate selective or conditional ligand binding based on context within the immune environment.

Transmembrane Domain:

• CLEC4C has a single transmembrane helix that anchors it in the plasma membrane of plasmacytoid dendritic cells. This domain stabilizes CLEC4C's position, enabling it to efficiently interact with extracellular ligands or pathogens. The transmembrane domain ensures that the receptor’s CTLD is presented on the cell surface, essential for ligand engagement and subsequent signal transduction.

Intracellular Tail:

• The intracellular region of CLEC4C contains motifs important for signaling upon ligand binding. Notably, this domain lacks intrinsic signaling motifs like the ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) found in other immune receptors. Instead, CLEC4C signaling is largely dependent on adapter proteins that associate with the cytoplasmic tail to transduce signals that can modulate interferon production and pDC function.

Glycosylation Sites:

• CLEC4C is a glycoprotein, with N-linked glycosylation sites that help maintain the stability and functionality of its extracellular CTLD. Glycosylation may influence ligand binding and receptor stability, optimizing CLEC4C’s role in immune recognition on pDCs.

Classification and Subtypes

CLEC4C is classified as part of the C-type lectin domain family (CLEC4), specifically within the subset that is associated with type II transmembrane receptors. This family encompasses receptors that share a similar structural CTLD but have diverse roles in immune regulation and pathogen recognition. CLEC4C itself does not have significant subtypes; however, it interacts closely with other CLR family members on dendritic cells, which allows it to coordinate immune responses through cooperative signaling pathways.

Function and Biological Significance

CLEC4C plays several roles in immune function, especially in relation to its expression on plasmacytoid dendritic cells (pDCs):

Pathogen Recognition:

• As a PRR, CLEC4C’s CTLD recognizes specific carbohydrate patterns on pathogens, enabling pDCs to detect viral or microbial presence. This interaction leads to pathogen binding and subsequent internalization by pDCs, which is crucial for initiating early immune responses to infections.

Regulation of Type I Interferon Production:

• When CLEC4C is cross-linked, it can inhibit the production of type I interferons by pDCs. This downregulation mechanism is crucial for modulating the immune response, as excessive production of type I interferons is associated with inflammatory and autoimmune conditions. Through this mechanism, CLEC4C acts as a negative feedback regulator, preventing excessive interferon release that could otherwise lead to tissue damage or chronic inflammation.

Role in Autoimmunity and Chronic Inflammatory Conditions:

• CLEC4C’s ability to modulate interferon production implicates it in autoimmune diseases like systemic lupus erythematosus (SLE), where aberrant pDC activation and excessive interferon production are common. CLEC4C’s regulation of pDC activity and cytokine secretion positions it as a potential therapeutic target in autoimmune conditions characterized by interferon dysregulation.

Immune Cell Trafficking and Antigen Presentation:

• CLEC4C facilitates pDC trafficking to lymphoid tissues and sites of infection, where these cells present antigens to T cells and secrete cytokines that guide adaptive immune responses. By regulating pDC function and migration, CLEC4C influences the balance between immune tolerance and activation, contributing to immune homeostasis and the prevention of inappropriate immune responses.

Clinical Issues

Due to its exclusive expression on pDCs and its role in modulating type I interferon production, CLEC4C is clinically relevant in several contexts:

Autoimmune Diseases:

• In conditions like systemic lupus erythematosus (SLE), elevated pDC activity and excessive interferon production contribute to chronic inflammation and immune dysregulation. CLEC4C’s ability to inhibit interferon production makes it a potential therapeutic target for reducing interferon-related pathology in SLE and similar autoimmune diseases. Therapies aimed at enhancing CLEC4C signaling could help downregulate interferon production, potentially alleviating autoimmune symptoms.

Chronic Viral Infections:

• Chronic viral infections, including hepatitis and HIV, involve dysregulated interferon responses that can contribute to immune exhaustion. Modulating CLEC4C activity may help control excessive immune activation and restore a balanced immune response in chronic infections. Studies are exploring the potential of targeting CLEC4C to modulate pDC responses in chronic viral infections, improving immune control without exacerbating inflammation.

Cancer Immunotherapy:

• pDCs play a role in tumor immunity, where their activity can either promote anti-tumor responses or contribute to immune tolerance within the tumor microenvironment. CLEC4C’s modulation of pDC function suggests it could influence immune cell behavior in cancers, making it a potential target for therapeutic strategies aiming to enhance anti-tumor immunity or prevent immune escape mechanisms. However, further studies are needed to fully understand CLEC4C’s impact on pDCs in cancer contexts.

Summary

CLEC4C, also known as CD303 or BDCA-2, is a type II transmembrane protein exclusively expressed on plasmacytoid dendritic cells (pDCs). It contains a C-type lectin-like domain (CTLD) that facilitates recognition and binding of carbohydrate structures on pathogens, playing a crucial role in pDC-mediated immune responses. Structurally, CLEC4C features an extracellular CTLD, a transmembrane domain, and an intracellular tail that interacts with adapter proteins to transduce signals.

Functionally, CLEC4C serves as a pathogen recognition receptor on pDCs, detecting viral and microbial components and facilitating immune responses. Importantly, CLEC4C modulates type I interferon production, acting as a feedback regulator to prevent excessive interferon release and potential immune-mediated tissue damage. In clinical settings, CLEC4C is relevant in autoimmune diseases, chronic infections, and potentially cancer immunotherapy. Its regulation of interferon production positions CLEC4C as a target for therapies aimed at controlling pDC activity, particularly in diseases where interferon dysregulation is implicated.

The study of CLEC4C continues to provide insights into immune modulation, pathogen recognition, and immune homeostasis, highlighting its importance in maintaining a balanced immune response and its potential as a therapeutic target in various immunological and inflammatory diseases.