LILRB2 - leukocyte immunoglobulin like receptor B2 |Elisa - Clia - Antibody - Protein

Background

LILRB2, also known as Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 2, ILT4 (Immunoglobulin-Like Transcript 4), or CD85d, is an inhibitory receptor expressed on immune cells, especially on myeloid cells, such as monocytes, macrophages, dendritic cells, and some granulocytes. It is part of the LILR family (leukocyte immunoglobulin-like receptors), which is encoded within the LRC (Leukocyte Receptor Complex) on chromosome 19q13.4. LILRB2 plays a major role in immune homeostasis by binding to MHC class I molecules and other ligands, leading to suppression of immune responses. This makes it a central player in controlling inflammation, self-tolerance, and response to chronic infections and tumors.

The primary role of LILRB2 is to inhibit myeloid cell activation and cytokine production, preventing excessive immune responses that could result in tissue damage. By recognizing self-MHC I molecules, LILRB2 helps immune cells distinguish between self and non-self, reducing the risk of autoimmunity. It has garnered attention for its role in modulating responses in various contexts, including cancer, chronic inflammation, and autoimmune diseases. Additionally, LILRB2's expression in tumor microenvironments contributes to immune evasion by tumors, which is why it is a target of interest in cancer immunotherapy.

Protein Structure

LILRB2 is a type I transmembrane protein consisting of an extracellular region for ligand binding, a single transmembrane domain, and a cytoplasmic tail with inhibitory signaling motifs.

Extracellular Domain (ECD):

• The extracellular region of LILRB2 contains four immunoglobulin-like (Ig-like) domains. These Ig-like domains provide structural integrity and enable LILRB2 to bind specifically to MHC class I molecules as well as other ligands that contribute to immune modulation.
• The binding interface on these Ig-like domains allows LILRB2 to recognize both self- and pathogen-associated ligands, which initiates a cascade of inhibitory signals that play a role in immune cell regulation. These domains are stabilized by disulfide bridges and contain conserved amino acid residues that facilitate interaction with MHC I molecules and other ligands.

Transmembrane Domain:

• LILRB2 has a single-pass transmembrane helix that anchors it to the cell membrane. This domain, while not involved in signal transduction itself, is essential for placing LILRB2 in the correct orientation on the cell surface and facilitating its interaction with extracellular ligands.

Intracellular Domain (Cytoplasmic Tail):

• The cytoplasmic tail of LILRB2 is essential for its inhibitory function, containing multiple immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These ITIMs are phosphorylated upon ligand binding and serve as docking sites for tyrosine phosphatases such as SHP-1 (Src homology region 2 domain-containing phosphatase-1) and SHP-2.
• Phosphorylation of the ITIMs allows LILRB2 to recruit these phosphatases, which dephosphorylate target signaling molecules in immune activation pathways, effectively dampening cell activation and cytokine production. This inhibition is crucial for reducing inflammatory responses, particularly during chronic infections or inflammatory conditions where sustained activation could cause tissue damage.

The structural configuration of LILRB2 is conserved across the LILR family, especially among the inhibitory receptors. This shared structural design allows LILRB2 to provide a robust inhibitory response across various immune challenges.

Classification and Subtypes

The LILR family is classified into two main groups: activating and inhibitory receptors. LILRB2 falls into the inhibitory receptor category, characterized by its intracellular ITIMs that mediate suppression of immune cell activation. It is one of five known LILRB receptors, which include:

1. LILRB1 - Highly similar in structure and function to LILRB2, primarily interacting with MHC class I molecules to inhibit immune activation.
2. LILRB2 - With a specific ligand-binding preference and inhibitory properties, it is the primary focus for immune modulation in chronic inflammation and cancer.
3. LILRB3, LILRB4, and LILRB5 - Other LILRB receptors with distinct ligand specificities and cell-type expressions, though sharing the inhibitory ITIMs in their cytoplasmic tails.

LILRB2 is closely related to LILRB1, which shares significant functional and structural homology. However, LILRB2 has unique ligand-binding characteristics, giving it distinct roles in immune modulation.

Function and Biological Significance

The primary functions of LILRB2 are immune suppression and the regulation of myeloid cell activation, helping maintain immune tolerance and prevent excessive immune responses.

Immune Suppression and Tolerance:

• By binding to self-MHC I molecules on healthy cells, LILRB2 delivers inhibitory signals to myeloid cells, preventing their overactivation. This suppression is critical for maintaining tolerance to self-antigens, thereby preventing autoimmunity.
• LILRB2-mediated suppression helps to modulate immune responses in chronic inflammation by controlling cytokine production and immune cell proliferation.

Regulation of Myeloid Cell Function:

• In monocytes and macrophages, LILRB2 reduces the release of inflammatory cytokines, protecting tissues from inflammation-induced damage. This role is particularly relevant in chronic inflammatory diseases where sustained immune activation could result in tissue injury.
• In dendritic cells, LILRB2 limits antigen presentation by reducing the expression of co-stimulatory molecules, thus lowering the activation threshold of T-cells. This downregulation helps maintain immune homeostasis by preventing excessive T-cell activation.

Cancer Immunity and Tumor Evasion:

• LILRB2 expression on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment enables tumors to evade immune detection. By dampening myeloid cell activation, LILRB2 contributes to an immunosuppressive environment that supports tumor growth.
• Inhibiting LILRB2 in cancer immunotherapy can restore anti-tumor immunity by reactivating immune cells, making it a promising target for therapies aimed at enhancing immune responses against tumors.

Response to Chronic Infections:

• In chronic infections, LILRB2 can help prevent overactivation of the immune system, reducing inflammation while allowing a controlled response to persistent pathogens. This balance is essential in infections where pathogen clearance is difficult, as unregulated immune responses could result in tissue damage.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of LILRB2 expression or function is implicated in autoimmune conditions. Insufficient inhibitory signaling may lead to uncontrolled immune activation, contributing to diseases like rheumatoid arthritis and systemic lupus erythematosus.
• Conversely, excessive LILRB2 activation may suppress beneficial immune responses, making it relevant to autoimmune disease therapies aimed at restoring immune balance.

Cancer:

• Tumors often exploit LILRB2’s immunosuppressive effects to avoid immune clearance. By engaging LILRB2 on immune cells, cancer cells can downregulate immune activity in the tumor microenvironment, promoting tumor growth and metastasis.
• Anti-LILRB2 antibodies and small-molecule inhibitors are currently under investigation to block this pathway, potentially reactivating anti-tumor immune responses and enhancing the effectiveness of other immunotherapies.

Chronic Inflammatory Diseases:

• LILRB2 modulation is beneficial in chronic inflammatory diseases like inflammatory bowel disease (IBD), where dampening immune activation could help control inflammation without compromising host immunity.
• Due to its regulatory role in immune cells, LILRB2 is a therapeutic target for reducing inflammatory damage in chronic conditions while preserving essential immune functions.

Transplantation:

• In transplantation settings, LILRB2 helps promote tolerance to allografts by inhibiting myeloid cell activation, which reduces the likelihood of immune-mediated graft rejection. Modulating LILRB2 activity is being explored as a potential strategy to improve graft survival rates by preventing immune rejection.

Summary

LILRB2 is an inhibitory immune receptor that plays a vital role in regulating immune responses through its interaction with MHC class I molecules and other ligands. Structurally, it consists of four extracellular Ig-like domains that bind ligands, a transmembrane domain anchoring it to the cell membrane, and a cytoplasmic tail with multiple ITIMs that mediate inhibitory signaling. By recruiting phosphatases such as SHP-1 and SHP-2, LILRB2 dampens immune activation, making it essential for immune tolerance, prevention of autoimmunity, and control of inflammation.

LILRB2 is implicated in a range of clinical contexts, including autoimmune diseases, chronic inflammation, cancer, and transplantation. Its immunosuppressive properties make it a double-edged sword: protective in conditions like autoimmunity and chronic inflammation, but detrimental in cancer, where it can contribute to tumor immune evasion. Targeting LILRB2 with specific inhibitors or antibodies has potential therapeutic applications, particularly in cancer immunotherapy and autoimmune disease management.