LILRB1 - leukocyte immunoglobulin like receptor B1 | Elisa - Clia - Antibody - Protein

Background

Leukocyte Immunoglobulin-Like Receptor B1 (LILRB1), also known as CD85j, ILT2, or LIR-1, is a member of the leukocyte immunoglobulin-like receptor (LILR) family that plays an important role in modulating immune responses. LILRB1 is classified as an inhibitory receptor due to its immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which enable it to dampen immune activation and promote immune tolerance. The LILR family consists of receptors involved in either activating or inhibiting immune responses, and they are predominantly expressed on myeloid and lymphoid cells, including monocytes, macrophages, dendritic cells, and natural killer (NK) cells.

LILRB1 is encoded by a gene located on chromosome 19q13.4 within a cluster of LILR family genes. Its expression pattern includes myeloid cells and subsets of lymphocytes, such as T cells and NK cells, indicating its wide-ranging roles in both innate and adaptive immunity. The receptor functions by binding to a broad spectrum of ligands, including major histocompatibility complex (MHC) class I molecules and human cytomegalovirus (HCMV) proteins. Through its inhibitory action, LILRB1 regulates immune responses, helping prevent excessive immune activity that can lead to tissue damage or autoimmune diseases.

Protein Structure

The structure of LILRB1 reflects its role as an inhibitory receptor, with domains that allow specific binding to ligands and signal inhibition.

Extracellular Region:

• The extracellular portion of LILRB1 contains four immunoglobulin-like (Ig-like) domains. These domains enable LILRB1 to interact with ligands, particularly MHC class I molecules, including both classical and non-classical forms, as well as certain viral proteins.
• Ig-like domains 1 and 2 are primarily responsible for ligand binding, especially to MHC class I molecules, through a mechanism involving recognition of β2-microglobulin-associated ligands.
• These Ig-like domains are stabilized by disulfide bridges, contributing to their structural integrity and allowing the receptor to interact efficiently with diverse ligands.

Transmembrane Domain:

• LILRB1 is a single-pass transmembrane protein with a hydrophobic segment that anchors it to the cell membrane. This structure facilitates its stable localization on the cell surface, enabling interactions with both extracellular ligands and intracellular signaling molecules.

Cytoplasmic Tail:

• The cytoplasmic tail of LILRB1 is crucial for its inhibitory function and contains four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). When LILRB1 binds to its ligands, these ITIMs are phosphorylated, recruiting phosphatases such as SHP-1 and SHP-2.
• These phosphatases dephosphorylate key signaling molecules within immune cells, effectively dampening activating signals and preventing excessive immune responses. This mechanism is essential for LILRB1’s role in promoting immune tolerance and preventing overactive immune responses.

Classification and Subtypes

LILRB1 belongs to the leukocyte immunoglobulin-like receptor family, which is subdivided into activating (LILRA) and inhibitory (LILRB) receptors. While activating LILRs, such as LILRA1 and LILRA3, contain ITAMs in their signaling adaptors, inhibitory LILRs, including LILRB1, contain ITIMs within their cytoplasmic tails, resulting in opposite functions.

Within the inhibitory group, LILRB1 is closely related to LILRB2, sharing structural similarities and overlapping ligand specificities. Although no known subtypes of LILRB1 exist, its functional diversity is influenced by cell type, activation state, and interaction with different ligands.

Function and Biological Significance

The primary role of LILRB1 is to modulate immune cell activity through inhibitory signaling. This function is essential for maintaining immune tolerance, preventing autoimmunity, and regulating immune responses to infections and tumors.

Immune Inhibition:

• LILRB1 interacts with MHC class I molecules, which are broadly expressed on most nucleated cells, providing a mechanism for immune cells to recognize “self” and restrain their activity accordingly. When LILRB1 binds MHC class I molecules, ITIM phosphorylation recruits SHP-1 and SHP-2 phosphatases, leading to the dephosphorylation of downstream signaling molecules and attenuating immune cell activation.
• This inhibitory signaling prevents overactive immune responses and helps maintain self-tolerance, especially in NK cells, which rely on LILRB1 to detect the presence of MHC class I as a “self” signal, thus avoiding attack on healthy cells.

Role in Pathogen Recognition:

• LILRB1 is involved in the immune response to certain pathogens, including human cytomegalovirus (HCMV), which produces proteins that mimic MHC class I to evade immune detection. By binding these viral proteins, LILRB1 can suppress immune activation in infected cells, creating an environment favorable for viral persistence.
• This interaction highlights how some pathogens exploit LILRB1’s inhibitory function to avoid immune clearance, underscoring the receptor’s complex role in infection dynamics.

Modulation of T Cell and NK Cell Activity:

• LILRB1 is expressed on T cells, where it acts as a checkpoint to restrain T cell activation. This function is particularly important in preventing overactivation in chronic infections and inflammatory diseases, where prolonged T cell activation can lead to tissue damage.
• In NK cells, LILRB1’s interaction with MHC class I molecules helps prevent “missing-self” recognition, a process that typically triggers NK cell cytotoxicity when MHC class I is absent, as seen in virally infected or tumor cells.

Immune Regulation in the Tumor Microenvironment:

• LILRB1 is increasingly recognized for its role in immune regulation within the tumor microenvironment. By dampening immune cell activation, LILRB1 can contribute to immune evasion by tumors that express MHC class I or other ligands that engage LILRB1.
• Consequently, LILRB1 has been considered a potential target for cancer immunotherapy. Blocking LILRB1 signaling could enhance anti-tumor immunity by reactivating immune cells suppressed within the tumor microenvironment.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of LILRB1 expression or signaling is associated with autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Reduced inhibitory signaling by LILRB1 can lead to an overactive immune response against self-antigens, contributing to autoimmune pathology.

Cancer:

• In the tumor microenvironment, LILRB1 contributes to immune evasion by inhibiting immune cell activity in response to MHC class I expression on tumor cells. This suppression enables tumor growth and metastasis by preventing effective immune surveillance. Consequently, LILRB1 is being investigated as a potential therapeutic target in cancer immunotherapy, with strategies aimed at blocking its inhibitory signals to restore anti-tumor immunity.

Infectious Diseases:

• LILRB1 plays a role in viral infections, particularly with viruses that exploit the receptor to evade immune responses. Human cytomegalovirus (HCMV) and other herpesviruses express MHC class I homologs that bind LILRB1, inhibiting immune responses against infected cells and promoting viral persistence.
• Given its role in infectious disease pathogenesis, LILRB1 may serve as a therapeutic target in infections where immune suppression is detrimental, such as in chronic viral infections.

Chronic Inflammatory Diseases:

• Chronic inflammatory conditions, including inflammatory bowel disease (IBD) and atherosclerosis, may involve dysregulated LILRB1 signaling, where excessive immune suppression contributes to the persistence of inflammation and immune dysregulation. Understanding LILRB1’s role in these diseases could provide insights into novel therapeutic strategies targeting its regulatory functions.

Summary

Leukocyte Immunoglobulin-Like Receptor B1 (LILRB1) is an inhibitory receptor predominantly expressed on myeloid cells, NK cells, and some T cell subsets. With four Ig-like extracellular domains, a single-pass transmembrane region, and a cytoplasmic tail containing four ITIMs, LILRB1 is well-suited to its role in immune inhibition. It modulates immune responses by binding MHC class I molecules and viral homologs, activating SHP-1 and SHP-2 phosphatases to suppress immune signaling pathways.

Functionally, LILRB1 is involved in maintaining immune tolerance, regulating T cell and NK cell activity, and modulating responses within the tumor microenvironment. Clinically, it plays a dual role: as a regulator in autoimmune diseases and chronic inflammation and as a potential therapeutic target in cancer and certain infectious diseases. As an inhibitory checkpoint, LILRB1 represents a key therapeutic target in oncology and immune modulation, where its inhibition could enhance anti-tumor and antiviral immunity while its activation could potentially aid in controlling autoimmunity and inflammatory disorders.