LILRA4 - leukocyte immunoglobulin like receptor A4 |Elisa - Clia - Antibody - Protein

Background

LILRA4 (Leukocyte Immunoglobulin-Like Receptor A4), also known as ILT7 or CD85g, is a member of the leukocyte immunoglobulin-like receptor (LILR) family, which is primarily involved in modulating immune responses. This receptor family is part of the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4, where several LILR family members are located, often associated with immune regulation. LILRA4 is distinct among LILRs as it is uniquely expressed on plasmacytoid dendritic cells (pDCs), a specialized dendritic cell subset primarily responsible for antiviral responses and producing type I interferons in response to viral infection. LILRA4 plays a suppressive role on pDCs by modulating interferon production, impacting immune responses, and helping maintain immune homeostasis.

The regulation of interferon responses by LILRA4 is crucial, particularly because excessive interferon production can contribute to inflammatory and autoimmune disorders. Consequently, LILRA4 is of interest in studying autoimmune conditions and chronic viral infections where pDC activity and interferon levels are dysregulated. LILRA4 engages in signaling by binding to FcεRIγ, an adaptor protein with immunoreceptor tyrosine-based activation motifs (ITAMs), which transduces inhibitory signals upon ligand engagement.

Protein Structure

LILRA4 has a distinctive structural organization compared to other LILR family members:

Extracellular Region (Ig-like Domains):

• LILRA4’s extracellular region contains two immunoglobulin-like (Ig-like) domains. These domains are highly conserved and play a central role in ligand binding and molecular stability. The Ig-like domains each comprise approximately 90-110 amino acids arranged in a beta-sheet configuration, stabilized by disulfide bridges, which create a compact structure ideal for ligand interaction.
• These Ig-like domains in LILRA4 are responsible for binding ligands, although the exact ligands for LILRA4 in vivo are still under investigation. Some studies suggest that LILRA4 may recognize MHC class I molecules or other yet-to-be-identified ligands associated with microbial or inflammatory responses.

Transmembrane Domain:

• LILRA4 possesses a single-pass transmembrane domain that anchors the receptor to the cell membrane. This transmembrane segment is essential for associating LILRA4 with the FcεRIγ signaling adaptor molecule. FcεRIγ contains ITAMs, crucial for transmitting inhibitory signals inside the cell upon LILRA4 engagement.
• The transmembrane region also contributes to the receptor’s overall stability on the cell surface, allowing LILRA4 to maintain its function in regulating pDC activity through effective ligand interaction and signal transduction.

Cytoplasmic Tail:

• The cytoplasmic tail of LILRA4 is relatively short and does not contain ITIMs (Immunoreceptor Tyrosine-based Inhibitory Motifs) or ITAMs. Instead, LILRA4 relies on FcεRIγ to transmit signals into the cell. When LILRA4 binds a ligand, the associated FcεRIγ molecule activates downstream signaling cascades that lead to suppression of interferon production.
• This signaling mechanism is unique within the LILR family, as most inhibitory LILRs contain ITIMs within their own cytoplasmic domains to transmit inhibitory signals. In LILRA4’s case, the reliance on FcεRIγ represents an alternative pathway for immunomodulation.

Classification and Subtypes

The LILR family includes both activating and inhibitory receptors that modulate immune responses. LILRA4 is classified within the activating LILR group, even though its function on pDCs often leads to an inhibitory outcome in the context of interferon production:

Activating Receptors:

• LILRA receptors, such as LILRA1, LILRA2, and LILRA4, are generally classified as activating receptors due to their association with ITAM-containing signaling molecules. This contrasts with inhibitory receptors (like LILRB1 and LILRB2), which have ITIMs for dampening immune responses.
• LILRA4 associates with FcεRIγ, an ITAM-bearing molecule that, upon ligand engagement, signals an inhibitory response specific to pDCs.

Soluble vs. Membrane-Bound Receptors:

• LILRA4 is a membrane-bound receptor with specific expression on plasmacytoid dendritic cells (pDCs). It is one of the more restricted members of the LILR family in terms of expression profile, primarily localized to a specialized subset of immune cells, unlike some LILR family members that are more broadly expressed on various leukocyte types.

LILRA4’s classification as an activating receptor reflects its structural association with ITAM-bearing adaptors, despite its primary role in inhibiting interferon production in pDCs.

Function and Biological Significance

LILRA4 plays a significant role in modulating immune responses through its interaction with FcεRIγ and subsequent impact on interferon production by plasmacytoid dendritic cells. Some of its primary functions include:

Regulation of Interferon Production:

• The main function of LILRA4 is to suppress type I interferon (IFN-α/β) production by pDCs. This is critical during chronic viral infections or in autoimmune diseases, where excessive interferon can exacerbate inflammation and tissue damage. Through its interaction with FcεRIγ, LILRA4 engagement prevents overstimulation of the immune system and helps maintain a balanced antiviral response.

Modulation of pDC Activation:

• LILRA4 dampens the activity of pDCs, which are central to initiating antiviral responses. By limiting pDC activation, LILRA4 indirectly regulates the broader immune response, preventing the development of chronic inflammatory states often associated with high levels of type I interferons.

Immune Homeostasis:

• By preventing excessive interferon responses, LILRA4 contributes to immune homeostasis. This regulatory role is particularly important in the context of autoimmune diseases, where unchecked interferon production can drive pathogenesis. LILRA4 helps maintain immune tolerance by modulating pDC function.

Potential Role in Tolerance and Antiviral Defense:

• LILRA4 may help in distinguishing between chronic and acute infections. By limiting interferon responses during chronic infections, LILRA4 aids in preventing tissue damage while allowing the immune system to effectively contain the virus.

The function of LILRA4 as an inhibitory receptor on pDCs reflects its essential role in balancing antiviral defenses with the need to prevent chronic inflammation and autoimmunity.

Clinical Issues

1. Autoimmune Diseases:

• Dysregulation of pDC activity and interferon production is a hallmark of several autoimmune diseases, including systemic lupus erythematosus (SLE) and psoriasis. Changes in LILRA4 expression or function can lead to excessive interferon responses, contributing to the inflammatory pathology observed in these diseases.
• Targeting LILRA4 or modulating its pathway is of therapeutic interest for autoimmune diseases where interferon dysregulation plays a central role. Therapies aimed at enhancing LILRA4 function may help reduce interferon-driven inflammation.

1. Chronic Viral Infections:

• Chronic viral infections, such as HIV and hepatitis C, often involve persistent pDC activation and interferon production, leading to immune exhaustion and inflammation. LILRA4’s ability to inhibit interferon production may provide therapeutic benefit by reducing chronic inflammation and allowing the immune system to focus on viral clearance.

1. Cancer:

• pDCs play a complex role in the tumor microenvironment, where they can either promote anti-tumor immunity or contribute to immune suppression. LILRA4 expression on pDCs within tumors might suppress interferon responses and favor immune evasion. Thus, modulating LILRA4 in cancer therapy could potentially enhance anti-tumor immunity.

1. Therapeutic Targeting:

• Due to its selective expression on pDCs and role in interferon regulation, LILRA4 is a promising therapeutic target. Strategies that aim to modulate LILRA4 function could provide therapeutic benefits in autoimmune diseases, chronic infections, and cancer.

Summary

LILRA4 is a unique member of the leukocyte immunoglobulin-like receptor family with specialized expression on plasmacytoid dendritic cells (pDCs). Structurally, it features two immunoglobulin-like domains, a transmembrane domain, and a short cytoplasmic tail. Unlike most LILRs, LILRA4 associates with the ITAM-bearing adaptor protein FcεRIγ to transduce inhibitory signals that modulate interferon production. Functionally, LILRA4 acts as an inhibitor of type I interferon production in pDCs, playing a critical role in controlling immune responses to prevent excessive inflammation, particularly in chronic viral infections and autoimmune diseases.

Clinically, LILRA4 is implicated in autoimmune disorders where dysregulation of interferon production by pDCs can lead to pathological inflammation. Modulating LILRA4 expression or function represents a promising therapeutic approach in autoimmune diseases, chronic infections, and cancer, where balancing interferon responses is crucial. LILRA4’s role in immune homeostasis and its potential as a therapeutic target underscore its importance in the broader context of immune regulation.