LILRB3 - leukocyte immunoglobulin like receptor B3 |Elisa - Clia - Antibody - Protein

Background

LILRB3 (Leukocyte Immunoglobulin-Like Receptor B3) is a member of the leukocyte immunoglobulin-like receptor (LILR) family, a group of receptors involved in regulating the immune response. LILRB3, also known as CD85A or ILT5 (Immunoglobulin-like Transcript 5), is predominantly expressed on myeloid cells, including monocytes, macrophages, neutrophils, and dendritic cells. These receptors play a crucial role in immune regulation by mediating inhibitory signals that prevent excessive activation of the immune system, contributing to the maintenance of immune homeostasis.

LILRB3 belongs to the inhibitory subfamily of LILR receptors, which means it primarily dampens immune responses. It achieves this through the recruitment of tyrosine phosphatases, which inhibit activating signaling pathways, thereby reducing inflammatory responses and promoting immune tolerance. This regulation is important for preventing autoimmune reactions and minimizing tissue damage during inflammatory processes.

The LILR gene family is located in a region on chromosome 19q13.4 and contains multiple members with varying functions. LILRB3 is one of the key inhibitory receptors in this family, balancing immune activation with inhibition, particularly in myeloid cells, where its role is significant in controlling responses to pathogens, tumor cells, and self-antigens.

Protein Structure

LILRB3 is a type I transmembrane protein, characterized by an extracellular domain involved in ligand binding, a transmembrane region that anchors the receptor in the cell membrane, and a cytoplasmic tail responsible for intracellular signaling. The structure of LILRB3 can be broken down into the following regions:

Extracellular Domain (ECD):

• The extracellular region consists of four immunoglobulin-like (Ig-like) domains. These domains are similar to those found in antibodies and are responsible for binding to various ligands, including major histocompatibility complex class I (MHC I) molecules. In addition to classical MHC I, LILRB3 can interact with non-classical MHC molecules and other ligands expressed on immune and non-immune cells.
• These interactions primarily result in inhibitory signals, preventing the overactivation of immune cells and promoting tolerance.
• The Ig-like domains contain disulfide bonds that stabilize the structure of the protein and maintain its functional integrity. The ligand-binding regions of these domains are critical for the modulation of immune responses.

Transmembrane Domain:

• LILRB3 has a single-pass transmembrane helix that anchors the receptor in the plasma membrane. This domain plays a key role in transmitting signals from the extracellular space into the cell.
• The transmembrane region does not directly participate in signal transduction but is crucial for the receptor's localization and interaction with other membrane proteins.

Intracellular Domain (Cytoplasmic Tail):

• The cytoplasmic domain of LILRB3 contains multiple immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These motifs are essential for the receptor's inhibitory function. When LILRB3 binds to its ligands, the ITIMs become phosphorylated, allowing them to recruit tyrosine phosphatases, such as SHP-1 and SHP-2 (Src homology region 2 domain-containing phosphatases).
• These phosphatases dephosphorylate signaling molecules downstream of activating receptors, thereby dampening the immune response. This mechanism is crucial for controlling immune cell activation, preventing excessive inflammation, and avoiding autoimmunity.
• The presence of multiple ITIMs enhances the receptor's ability to deliver potent inhibitory signals.

Classification and Subtypes

LILRB3 is classified as part of the leukocyte immunoglobulin-like receptor (LILR) family, which includes both activating and inhibitory receptors. LILR receptors are further subdivided into two main groups:

1. Activating Receptors (e.g., LILRA1, LILRA2): These receptors contain immunoreceptor tyrosine-based activating motifs (ITAMs) in their cytoplasmic tails or associate with adaptor proteins that have ITAMs. They promote immune cell activation by interacting with specific ligands, such as MHC I molecules.
2. Inhibitory Receptors (e.g., LILRB1, LILRB2, LILRB3, LILRB4, LILRB5): These receptors contain ITIMs in their cytoplasmic domains and primarily function to inhibit immune cell activation by recruiting phosphatases like SHP-1 and SHP-2. LILRB3 belongs to this inhibitory subgroup.

LILRB3 is specifically expressed on myeloid cells and shares structural and functional similarities with other LILRB receptors. While LILRB1 and LILRB2 are more widely expressed and well-studied, LILRB3 has a more restricted expression pattern and unique regulatory roles in myeloid immune responses.

Function and Biological Significance

LILRB3 plays a significant role in immune regulation, particularly by inhibiting immune cell activation and inflammatory responses. The primary functions of LILRB3 include:

Immune Inhibition:

• By interacting with MHC class I molecules, LILRB3 delivers inhibitory signals that reduce the activation of myeloid cells. This inhibition helps maintain immune tolerance, preventing the immune system from attacking healthy tissues and avoiding autoimmunity.
• LILRB3 also modulates responses to pathogens and tumor cells. It can suppress excessive immune activation, which is important in preventing tissue damage during chronic infections or inflammatory diseases.

Regulation of Myeloid Cell Functions:

• LILRB3 is expressed on monocytes, macrophages, and dendritic cells, where it regulates key functions such as cytokine production, antigen presentation, and phagocytosis. By inhibiting these processes, LILRB3 ensures that immune responses are properly controlled, preventing overactivation that could lead to chronic inflammation.
• In neutrophils, LILRB3 helps modulate their activation and migration, impacting their role in innate immunity and inflammation.

Maintenance of Immune Homeostasis:

• LILRB3 contributes to the maintenance of immune homeostasis by regulating the balance between immune activation and inhibition. This balance is crucial in conditions where inappropriate immune activation could lead to autoimmune disorders or tissue damage.
• In tumor immunity, LILRB3 can play a dual role by either dampening anti-tumor immune responses or preventing excessive inflammation that could promote tumor progression.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of LILRB3 function has been implicated in the development of autoimmune diseases. Overactivity of LILRB3 may lead to excessive inhibition of immune responses, contributing to immune tolerance of autoreactive cells. Conversely, reduced LILRB3 function could lead to excessive immune activation and autoimmune damage.

Cancer:

• In the context of cancer, LILRB3 expression on tumor-associated macrophages (TAMs) and other myeloid cells can suppress effective anti-tumor immune responses, promoting tumor progression. However, targeting LILRB3 in cancer therapy is being explored as a potential way to restore immune activation and enhance anti-tumor immunity.
• On the other hand, LILRB3’s role in maintaining immune tolerance may also help prevent excessive immune responses that could lead to tissue damage during cancer immunotherapy.

Chronic Infections:

• LILRB3 is also involved in regulating immune responses during chronic infections. By dampening immune activation, LILRB3 can prevent tissue damage caused by persistent inflammation but may also contribute to the persistence of pathogens by inhibiting effective immune clearance.

Inflammatory Diseases:

• In conditions like chronic inflammatory diseases (e.g., rheumatoid arthritis or inflammatory bowel disease), dysregulated LILRB3 signaling may contribute to either insufficient immune control or excessive inflammation, depending on the context.

Summary

LILRB3 is a key inhibitory receptor that plays a crucial role in maintaining immune homeostasis by regulating the activation of myeloid cells. Structurally, it is a type I transmembrane protein with four extracellular Ig-like domains, a transmembrane helix, and a cytoplasmic tail containing ITIMs that recruit phosphatases to inhibit immune cell activation. LILRB3 is primarily expressed on monocytes, macrophages, neutrophils, and dendritic cells, where it modulates functions such as cytokine production, antigen presentation, and inflammatory responses.

LILRB3’s role in immune regulation makes it a critical molecule for controlling autoimmune responses, tumor immunity, and chronic inflammation. Dysregulation of LILRB3 signaling is associated with various clinical conditions, including autoimmune diseases, cancer, and chronic infections. Understanding the molecular mechanisms of LILRB3 function and its interactions with other immune receptors is essential for developing potential therapeutic strategies targeting this receptor in a wide range of immune-related diseases.