LY9 - lymphocyte antigen 9 |Elisa - Clia - Antibody - Protein

Background

Lymphocyte antigen 9 (LY9), also known as SLAMF3 (Signaling Lymphocytic Activation Molecule Family Member 3), is a transmembrane glycoprotein and member of the immunoglobulin (Ig) superfamily. This molecule is part of the broader SLAM family, a set of proteins primarily expressed on immune cells. LY9, like other SLAM family members, plays a key role in immune cell signaling, cell-to-cell interactions, and immunoregulation, specifically in adaptive immunity. This protein is highly expressed on lymphocytes, particularly T cells and natural killer (NK) cells, and it is involved in mediating various immune responses by interacting with other immune cells.

LY9 participates in homotypic interactions, meaning it binds to another LY9 molecule on adjacent cells, facilitating immune cell communication and signaling. Its expression is primarily associated with lymphoid tissues, but it is also present on other immune cells, where it regulates responses by activating intracellular signaling cascades. Studies show that LY9 contributes to immune regulation by affecting processes such as cytokine secretion, cytotoxicity, and immune cell differentiation. Given its involvement in immune signaling, LY9 is being investigated as a therapeutic target in conditions where immune regulation is disrupted, including autoimmune diseases, cancers, and immunodeficiencies.

Protein Structure

LY9 is a type I transmembrane protein with several distinct structural domains:

Extracellular Domain:

• The extracellular domain of LY9 contains four immunoglobulin-like domains (Ig domains), each with specific roles in mediating homotypic interactions and ligand binding. The structure of these Ig domains is similar to other immunoglobulin family proteins and is essential for LY9’s role in immune cell adhesion and signaling.
• Each Ig domain comprises a set of antiparallel β-strands that form a β-sheet structure, stabilized by disulfide bridges. These β-strands provide structural stability and support LY9's interactions with other LY9 molecules on adjacent immune cells. The extracellular domain’s configuration allows for the homotypic binding that is crucial for signal transduction between immune cells.

Transmembrane Domain:

• The transmembrane region of LY9 is composed of a single α-helix that spans the cell membrane, anchoring the protein within the lipid bilayer. This transmembrane helix helps in positioning the extracellular Ig domains and the intracellular signaling domains, aligning them for effective communication between cells.

Intracellular Domain:

• The cytoplasmic domain of LY9 contains several signaling motifs and tyrosine-based motifs, which are phosphorylated upon receptor activation. These motifs include immunoreceptor tyrosine-based switch motifs (ITSMs) that are critical for initiating downstream signaling pathways.
• When phosphorylated, the ITSMs serve as docking sites for signaling proteins such as SH2 domain-containing proteins. This enables interactions with adaptor molecules like SLAM-associated protein (SAP) and EWS-FLI1 activated transcript 2 (EAT-2), which are essential for propagating immune signals. Through these signaling pathways, LY9 can modulate various immune responses, including cytokine production, immune cell adhesion, and cytotoxicity.

Classification and Subtypes

LY9 belongs to the SLAM family within the immunoglobulin superfamily, which includes other molecules like SLAMF1 (CD150), CD229 (Ly9), CD244, and CD48. These molecules share structural similarities, including Ig-like domains and ITSMs, which facilitate their roles in immune cell signaling and regulation. The SLAM family proteins are involved in the modulation of immune cell activation, differentiation, and communication.

There are no major subtypes of LY9, but splice variants exist that may result in minor differences in protein expression or function. These variants are still under investigation, with current research focused on their potential impact on immune regulation and their roles in different cell types.

Function and Biological Significance

LY9 is primarily involved in immune cell signaling, playing critical roles in:

Immune Cell Adhesion and Interaction:

• LY9’s extracellular domains facilitate homotypic binding, which is essential for maintaining stable cell-cell interactions between immune cells such as T cells, B cells, and NK cells. These interactions allow immune cells to communicate effectively, modulating immune responses and ensuring coordinated action against pathogens.
• By forming stable connections with other LY9 molecules on adjacent cells, LY9 ensures precise spatial arrangement for immune synapse formation, especially in T cells and NK cells, facilitating effective antigen recognition and response.

Signal Transduction:

• LY9's ITSM motifs activate signaling pathways by recruiting adaptor molecules like SAP and EAT-2, which are essential for the initiation of downstream signaling events. Through these pathways, LY9 modulates key functions such as cytotoxicity, cytokine production, and cell survival.
• In T cells, for instance, LY9 signaling can promote cytokine secretion, enhancing T cell activation and proliferation. In NK cells, LY9 engagement can enhance cytotoxicity, aiding in the clearance of infected or transformed cells.

Immune Homeostasis and Regulation:

• LY9 plays a regulatory role by modulating immune cell activation thresholds and maintaining immune homeostasis. This is particularly important in preventing autoimmune reactions, as LY9 signaling helps in distinguishing self from non-self and in regulating the strength of immune responses.
• Additionally, LY9 has been shown to be involved in immune tolerance mechanisms, which are crucial in preventing excessive immune activation and autoimmunity. Through its interactions with other SLAM family members, LY9 can inhibit or modulate immune responses, depending on the cellular context and immune environment.

Role in Immune Disorders and Cancer:

• LY9’s involvement in immune signaling makes it a key player in autoimmune diseases and cancer. Alterations in LY9 expression or function have been observed in certain cancers and autoimmune conditions, where immune signaling is dysregulated. In cancer, LY9 expression on tumor-infiltrating lymphocytes (TILs) may influence anti-tumor immunity, either promoting or inhibiting immune responses.

Clinical Issues

Abnormalities in LY9 expression and function have been linked to various pathological conditions:

Autoimmune Diseases:

• Aberrant expression or signaling of LY9 has been implicated in autoimmune disorders such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Dysregulated LY9 signaling may contribute to loss of immune tolerance, leading to the immune system attacking self-antigens.
• In these conditions, LY9 signaling may enhance T and B cell activation, promoting the production of autoantibodies and inflammatory cytokines. Research is ongoing to determine if targeting LY9 could help restore immune tolerance in these diseases.

Cancer:

• In certain cancers, altered LY9 expression on immune cells may contribute to tumor immune evasion. For example, LY9 expression on T cells within the tumor microenvironment may influence T cell activation and cytotoxicity, either promoting or hindering anti-tumor immunity.
• As a result, LY9 is being investigated as a potential target for immunotherapy. Modulating LY9 activity in the tumor microenvironment could help boost the immune system’s ability to recognize and destroy cancer cells.

Primary Immunodeficiencies:

• Mutations or deficiencies in LY9 and other SLAM family members are associated with primary immunodeficiency syndromes, where patients suffer from recurrent infections due to compromised immune function. These conditions are often characterized by defects in T cell and NK cell signaling, underscoring the importance of LY9 in immune health.

Summary

LY9, or lymphocyte antigen 9, is a transmembrane protein in the SLAM family that plays critical roles in immune cell adhesion, signaling, and regulation. Structurally, LY9 has an extracellular domain with immunoglobulin-like regions for cell-cell interaction, a transmembrane domain that anchors it within the cell membrane, and an intracellular domain containing ITSMs that activate downstream signaling pathways. These signaling pathways involve adaptor proteins like SAP and EAT-2, enabling LY9 to modulate immune responses.

Functionally, LY9 is involved in immune cell adhesion, signal transduction, and immune regulation. Through its interactions with other SLAM family proteins, LY9 contributes to immune homeostasis and tolerance, preventing excessive immune activation. Dysregulation of LY9 has been linked to autoimmune diseases, cancer, and immunodeficiency syndromes, making it a potential target for therapeutic intervention. Current research on LY9 focuses on understanding its role in immune disorders and exploring its potential as an immunotherapeutic target in diseases where immune regulation is impaired.