LILRB4 - leukocyte immunoglobulin like receptor B4 |Elisa - Clia - Antibody - Protein

Background

Leukocyte Immunoglobulin-Like Receptor B4 (LILRB4), also known as CD85K, ILT3, or LIR-5, is an inhibitory receptor expressed mainly on myeloid cells, such as dendritic cells, macrophages, and monocytes. As a member of the leukocyte immunoglobulin-like receptor (LILR) family, it functions primarily to suppress immune responses, maintaining immune homeostasis and preventing overactivation. LILRB4’s immune-modulatory role is particularly crucial in preventing autoimmune reactions and regulating inflammatory responses. Its expression is primarily restricted to cells of the myeloid lineage, making it a key component in myeloid cell function. The gene encoding LILRB4 is located within a cluster of LILR genes on chromosome 19q13.4, close to other LILR genes, which are involved in immune modulation.

Protein Structure

LILRB4’s protein structure is specifically adapted for its role as an inhibitory receptor, with a configuration that enables binding to ligands and transmitting inhibitory signals upon activation.

Extracellular Region:

• The extracellular portion of LILRB4 is composed of two immunoglobulin-like (Ig-like) domains, which are structurally similar to other members of the immunoglobulin superfamily. These domains are responsible for ligand recognition and binding, although LILRB4's ligand specificity is somewhat limited compared to other LILRs.
• The Ig-like domains are stabilized by disulfide bonds, which provide structural integrity, allowing the receptor to effectively engage ligands. This extracellular region allows it to recognize and bind to certain molecules, like MHC class I and some other host or microbial molecules.

Transmembrane Domain:

• LILRB4 is a single-pass transmembrane protein, meaning it crosses the cell membrane once. This configuration anchors it to the cell membrane, allowing it to interface between extracellular ligand recognition and intracellular signaling.

Cytoplasmic Tail:

• The cytoplasmic tail of LILRB4 is critical for its inhibitory function. It contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). When LILRB4 binds to its ligands, the ITIMs undergo phosphorylation, which then recruits phosphatases like SHP-1 and SHP-2.
• These phosphatases act to dephosphorylate signaling molecules within the immune cell, effectively blocking downstream activating signals. This inhibitory action reduces the activity of pro-inflammatory pathways, thus suppressing immune activation.

Classification and Subtypes

LILRB4 is a member of the leukocyte immunoglobulin-like receptor (LILR) family, classified within the LILRB subgroup due to its inhibitory function mediated by ITIMs. Unlike activating LILRs, which contain ITAMs for signal transduction, LILRB4's ITIM-containing cytoplasmic tail places it within the inhibitory category, designed to dampen immune responses rather than stimulate them.

Among LILRs, LILRB4 shares a functional resemblance to other inhibitory receptors, such as LILRB1 and LILRB2, although its ligand specificity and expression pattern are more restricted to myeloid cells. No subtypes of LILRB4 have been identified; however, its expression levels can vary based on cell type, immune status, and disease context, which can influence its function in immune regulation.

Function and Biological Significance

The main function of LILRB4 is to inhibit immune responses, particularly those associated with inflammation and autoimmunity. This receptor plays a central role in regulating the activity of myeloid cells and controlling immune responses, especially in tissues with high inflammation or immune activation.

Immune Inhibition and Maintenance of Tolerance:

• LILRB4 provides a checkpoint for immune cells, especially dendritic cells and macrophages, helping to maintain tolerance and preventing inappropriate activation. By engaging with specific ligands, LILRB4 triggers a cascade of inhibitory signals that recruit phosphatases like SHP-1 and SHP-2. These phosphatases dampen immune signaling pathways that could otherwise lead to excessive activation of immune cells, contributing to immune homeostasis and self-tolerance.
• This inhibitory effect is essential for preventing autoimmune responses, as it helps maintain a balance in immune activation by providing negative feedback to activated immune cells.

Regulation of Dendritic Cell Function:

• LILRB4 plays a critical role in dendritic cell biology by inhibiting their maturation and antigen-presenting capabilities. By inhibiting dendritic cell activation, LILRB4 limits T cell stimulation, thus reducing T cell-mediated immune responses. This function is especially important in preventing autoimmunity and controlling immune responses during chronic inflammation.

Role in Inflammation and Infection:

• LILRB4’s inhibitory effect on myeloid cells helps to control inflammatory responses during infection and injury. By reducing the activity of macrophages and dendritic cells, LILRB4 can mitigate tissue damage caused by excessive inflammation. This makes LILRB4 important for resolving inflammation and preventing tissue damage, especially in chronic inflammatory conditions.
• During infections, certain pathogens may exploit LILRB4's inhibitory function to evade immune clearance, as LILRB4 activation can suppress the immune response against pathogens.

Inhibition of Pro-inflammatory Cytokine Production:

• LILRB4 downregulates the production of pro-inflammatory cytokines, such as IL-6 and TNF-α, in myeloid cells. This regulatory action helps limit inflammation and prevents the overproduction of cytokines, which could otherwise lead to cytokine storm conditions. This control of cytokine levels is vital in both chronic inflammatory conditions and immune responses to infections.

Clinical Issues

Autoimmune Diseases:

• Given its role in maintaining immune tolerance, dysregulation of LILRB4 is associated with autoimmune diseases. Reduced expression or function of LILRB4 may result in increased activation of dendritic cells and macrophages, leading to overactivation of the immune system and promoting autoimmune pathologies.

Cancer:

• LILRB4 is increasingly recognized for its role in the tumor microenvironment, where it can suppress anti-tumor immunity. Cancer cells may exploit LILRB4’s inhibitory function by engaging this receptor on dendritic cells or macrophages, reducing immune activation within the tumor microenvironment. This suppression aids in tumor immune evasion and contributes to cancer progression.
• LILRB4 is currently being investigated as a therapeutic target for cancer immunotherapy. Inhibitors that block LILRB4 could potentially enhance anti-tumor immunity by reactivating immune cells suppressed within the tumor microenvironment.

Chronic Inflammatory Conditions:

• Chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, are characterized by prolonged immune activation and tissue damage. LILRB4’s inhibitory function may be impaired in these conditions, contributing to sustained inflammation and disease progression.

Infectious Diseases:

• Some pathogens may exploit LILRB4’s inhibitory mechanism to escape immune detection. By binding to or activating LILRB4, pathogens like certain bacteria and viruses can suppress immune responses, allowing them to persist in the host. This exploitation of LILRB4 contributes to chronic infections and complicates immune clearance.

Summary

LILRB4, or CD85K, is an inhibitory receptor primarily expressed on myeloid cells, playing a central role in immune modulation. Structurally, it consists of two extracellular Ig-like domains, a single transmembrane region, and a cytoplasmic tail with two ITIMs that mediate its inhibitory signaling. Through these ITIM motifs, LILRB4 recruits phosphatases to attenuate downstream immune signaling, reducing cell activation, cytokine production, and antigen presentation. Its primary function is to prevent overactivation of myeloid cells, thus contributing to immune tolerance, controlling inflammation, and maintaining immune homeostasis.

In terms of clinical implications, LILRB4’s role in immune regulation makes it a factor in various diseases. Dysregulation of LILRB4 is associated with autoimmune conditions due to unchecked immune activation. In cancer, LILRB4 contributes to immune evasion within the tumor microenvironment, making it a target for cancer immunotherapy. Moreover, in chronic inflammatory conditions and infectious diseases, LILRB4 is implicated in immune suppression, which can be exploited by pathogens to evade host immunity. Given its central role in immune modulation, LILRB4 is an important target in the development of therapies aimed at modulating immune responses in autoimmunity, cancer, and chronic inflammation.