LILRB5 - leukocyte immunoglobulin like receptor B5 |Elisa - Clia - Antibody - Protein

Background

LILRB5 (Leukocyte Immunoglobulin-Like Receptor B5), also known as ILT7 or CD85c, is part of the LILR (leukocyte immunoglobulin-like receptor) family, which plays a pivotal role in immune regulation. The LILR family includes activating and inhibitory receptors expressed on immune cells, primarily myeloid cells. LILRB5, an inhibitory receptor, is encoded within a highly polymorphic region on chromosome 19q13.4. The inhibitory receptors in this family, including LILRB5, interact with major histocompatibility complex (MHC) molecules and other ligands, modulating immune responses and promoting tolerance, particularly in tissues prone to autoimmune inflammation or where immune homeostasis is critical.

LILRB5 expression is seen in monocytes, macrophages, neutrophils, and dendritic cells. Its function is primarily to transmit inhibitory signals that suppress overactive immune responses, which helps protect tissues from damage during prolonged immune activation or chronic inflammatory diseases. LILRB5’s interactions with both self and foreign ligands make it a key player in modulating immune responses to various stimuli, from infection to cancer and autoimmunity. By modulating the activity of myeloid cells, LILRB5 plays a central role in balancing immune activation with immune suppression, allowing the immune system to respond effectively without causing excessive inflammation or damage to host tissues.

Protein Structure

LILRB5 is a type I transmembrane protein composed of distinct domains: the extracellular domain, transmembrane domain, and intracellular cytoplasmic tail. This structure allows it to perform ligand binding and signal transduction.

Extracellular Domain (ECD):

• The extracellular region of LILRB5 contains four immunoglobulin-like (Ig-like) domains, which are responsible for binding ligands. The structure is stabilized by disulfide bonds within each domain, which contribute to its stability and enable it to interact with various ligands, including MHC class I molecules and other immune modulatory proteins.
• These Ig-like domains are characteristic of immunoglobulin receptors and help LILRB5 recognize and bind to self or foreign antigens, initiating downstream signaling upon ligand binding.
• The ligand-binding interface on these domains is highly conserved among other members of the LILR family, allowing it to interact with a range of ligands involved in immune response regulation.

Transmembrane Domain:

• LILRB5 has a single-pass transmembrane helix, which anchors the receptor to the plasma membrane. This domain ensures that the extracellular domain is correctly positioned to interact with ligands outside the cell while facilitating signal transduction from extracellular interactions to intracellular signaling pathways.
• While the transmembrane region does not directly participate in signal transduction, it is essential for the structural integrity and proper localization of LILRB5 within the membrane.

Intracellular Domain (Cytoplasmic Tail):

• The intracellular domain of LILRB5 contains multiple immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These ITIMs are phosphorylated upon ligand binding, enabling LILRB5 to recruit tyrosine phosphatases, such as SHP-1 and SHP-2. This recruitment and subsequent dephosphorylation events lead to the inhibition of downstream signaling pathways, effectively reducing cellular activation and inflammation.
• The presence of multiple ITIMs enhances LILRB5’s inhibitory effect, which is critical for its function in modulating immune responses.

The structural features of LILRB5 allow it to serve as a robust inhibitor of immune activation in myeloid cells, fine-tuning responses to various immune challenges.

Classification and Subtypes

LILRB5 belongs to the LILRB subclass within the LILR family. The LILR family is categorized into two major groups:

1. Activating Receptors (e.g., LILRA1, LILRA2): These receptors contain immunoreceptor tyrosine-based activation motifs (ITAMs) and promote immune activation. Activating receptors generally work in tandem with inhibitory receptors to balance immune cell activation.
2. Inhibitory Receptors (e.g., LILRB1, LILRB2, LILRB3, LILRB4, LILRB5): These receptors contain ITIMs and primarily serve to inhibit immune responses. LILRB5, specifically, is unique in that it is primarily expressed on myeloid cells and specializes in controlling immune cell activation by recruiting phosphatases that dampen immune signaling.

LILRB5 is most closely related to LILRB4 and LILRB3, which are also myeloid-specific inhibitory receptors. It lacks the cytotoxic signaling potential seen in some LILR family members, focusing exclusively on suppressing immune activation and inflammatory responses.

Function and Biological Significance

The main functions and significance of LILRB5 include:

Immune Suppression and Regulation:

• LILRB5 plays a critical role in immune inhibition, acting as a checkpoint in immune responses to prevent overactivation. By recruiting phosphatases through its ITIMs, LILRB5 dampens activating signals in myeloid cells, effectively reducing cytokine production and cellular proliferation.
• This inhibition prevents excessive inflammation and reduces the risk of immune-mediated tissue damage, especially in organs susceptible to inflammatory damage, such as the lungs and liver.

Regulation of Myeloid Cell Activity:

• In monocytes and macrophages, LILRB5 modulates responses to pathogens and tissue damage, preventing overproduction of pro-inflammatory cytokines. This function is essential during chronic infections or long-term exposure to inflammatory stimuli, where immune responses must be tightly regulated to avoid host tissue damage.
• LILRB5 is also expressed in dendritic cells, where it can influence antigen presentation by inhibiting activation signals. This allows LILRB5 to help maintain immune tolerance, especially in tissues where autoantigens are present.

Promotion of Immune Homeostasis:

• By acting as an inhibitory receptor, LILRB5 helps maintain immune homeostasis in the body. Its regulation of myeloid cell activity prevents the development of autoimmune diseases and controls chronic inflammation.
• LILRB5’s role in balancing activation and inhibition is crucial in environments where immune tolerance is required, such as during exposure to self-antigens or in cases of tissue transplantation.

Modulation of Cancer Immunity:

• LILRB5 is involved in the immune system's response to tumor cells. By inhibiting immune responses in the tumor microenvironment, LILRB5 can contribute to immune evasion, allowing tumor cells to escape detection and destruction by the immune system. However, LILRB5’s role in cancer immunity remains an area of active research.

Clinical Issues

Autoimmune Disorders:

• Dysregulation of LILRB5 function can contribute to autoimmune diseases. Insufficient inhibitory signaling may lead to excessive immune activation, potentially leading to conditions such as rheumatoid arthritis and lupus.
• Conversely, overactive LILRB5 signaling may dampen necessary immune responses, promoting immune tolerance to autoreactive cells.

Cancer:

• In the context of cancer, the expression of LILRB5 on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) has been implicated in tumor progression. The immunosuppressive effects of LILRB5 can promote an environment that supports tumor growth and protects cancer cells from immune destruction.
• As a result, LILRB5 is a potential target for cancer immunotherapy. Inhibiting LILRB5 may help restore immune activation against tumors, thereby enhancing anti-tumor immunity.

Chronic Inflammatory Diseases:

• Chronic inflammatory conditions, such as inflammatory bowel disease (IBD), are associated with dysregulation of immune responses, where LILRB5 plays a role in limiting the extent of inflammation. LILRB5 is thus a target of interest in therapies aimed at reducing inflammation without compromising immunity.

Transplantation and Allograft Rejection:

• In transplantation, LILRB5 may help prevent allograft rejection by promoting immune tolerance to the transplanted organ. Modulating LILRB5 activity could improve transplantation outcomes by reducing the risk of immune-mediated rejection.

Summary

LILRB5 is a critical inhibitory receptor within the leukocyte immunoglobulin-like receptor (LILR) family that plays a major role in regulating immune responses, especially in myeloid cells. Structurally, it is a type I transmembrane protein with four extracellular Ig-like domains for ligand binding, a single transmembrane helix, and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These structural features enable LILRB5 to bind to ligands, such as MHC I molecules, and initiate inhibitory signaling that recruits tyrosine phosphatases like SHP-1 and SHP-2, ultimately suppressing cellular activation.

LILRB5’s primary functions involve immune suppression, myeloid cell regulation, and maintenance of immune homeostasis. Clinically, LILRB5 is associated with a range of diseases, from autoimmune disorders and chronic inflammation to cancer. Its role in balancing immune responses makes it a potential therapeutic target in cancer immunotherapy, autoimmune disease management, and transplantation. LILRB5’s ability to fine-tune immune activity highlights its importance in both health and disease.