SLAMF8 - SLAM family member 8 |Elisa - Clia - Antibody - Protein

Background

SLAMF8 (Signaling Lymphocytic Activation Molecule Family Member 8) is a cell-surface receptor protein that is part of the SLAM (Signaling Lymphocyte Activation Molecule) family, a subgroup of the immunoglobulin (Ig) superfamily. SLAM family receptors, including SLAMF8, are involved in immune cell communication, with significant roles in immune regulation and inflammation. SLAMF8 is expressed primarily on macrophages, dendritic cells, neutrophils, and monocytes and is notable for its involvement in immune cell activation, particularly in response to infections and inflammatory stimuli.

Unlike other SLAM family members, SLAMF8 does not interact with the adaptor molecule SAP (SLAM-associated protein) for signaling. Instead, it appears to have a distinctive signaling pathway, involving interactions with other signaling molecules to modulate immune responses. SLAMF8 has been implicated in the regulation of reactive oxygen species (ROS) production, phagocytosis, and inflammatory cytokine production, which contribute to the host defense against pathogens. It plays an important role in modulating innate immune responses, helping balance pro- and anti-inflammatory signals during infection and inflammation.

Protein Structure

SLAMF8 is a type I transmembrane protein composed of approximately 220 amino acids. The structural features of SLAMF8 include:

Extracellular Domain:

• The extracellular domain of SLAMF8 contains a single Ig-like V-set domain, typical of SLAM family members. This domain is responsible for mediating interactions with other cell-surface molecules or with itself in homophilic interactions.
• The extracellular domain has glycosylation sites that stabilize the structure, assist in proper folding, and help in receptor-ligand interactions. These glycosylation modifications are also important for the receptor’s interaction with other cell-surface proteins and maintaining protein stability.

Transmembrane Domain:

• SLAMF8’s transmembrane region is composed of a single hydrophobic α-helix that anchors the protein within the lipid bilayer. This domain is critical for maintaining SLAMF8’s position on the cell surface, where it can interact with other receptors or ligands in the microenvironment of immune cells.

Cytoplasmic (Intracellular) Domain:

• Unlike other SLAM family members, SLAMF8 lacks the conventional immunoreceptor tyrosine-based switch motifs (ITSMs) found in most SLAM receptors. Instead, SLAMF8 has a short cytoplasmic tail with alternative tyrosine residues and motifs that are not associated with SAP but instead may interact with different intracellular molecules.
• This unique structure results in distinct signaling properties. While most SLAM family receptors rely on SAP to transmit signals, SLAMF8 engages with other intracellular adaptors and kinases to influence immune cell function. This independence from SAP-mediated signaling defines a unique signaling mechanism among SLAM receptors and highlights its non-SAP-dependent functions in immune cell regulation.

Classification and Subtypes

SLAMF8 belongs to the SLAM family within the larger immunoglobulin superfamily, which includes several related receptors such as SLAMF1 (CD150), SLAMF2 (CD48), SLAMF3, SLAMF4, and SLAMF7. These receptors are primarily associated with modulating immune responses, particularly in lymphocytes and other immune cells. SLAMF8 does not have known subtypes or isoforms, but it shares structural and functional similarities with other SLAM family members, though with a unique non-SAP-dependent signaling mechanism.

Function and Biological Significance

Modulation of Immune Cell Activation:

• SLAMF8 plays a regulatory role in the activation and function of macrophages, neutrophils, and dendritic cells. In macrophages, SLAMF8 is involved in modulating responses to bacterial lipopolysaccharide (LPS) and other pathogen-associated molecular patterns (PAMPs) that trigger immune activation.
• It contributes to the regulation of reactive oxygen species (ROS) production in phagocytes, aiding in the neutralization and destruction of pathogens during infection. By modulating ROS production, SLAMF8 helps control inflammation and limit tissue damage that can result from excessive ROS release.

Role in Phagocytosis and Inflammation:

• SLAMF8 is implicated in the regulation of phagocytic activity, where it plays a role in clearing pathogens and cell debris. By modulating phagocytosis, SLAMF8 ensures that immune cells respond appropriately to pathogens without excessive inflammation.
• Additionally, SLAMF8 regulates the production of pro-inflammatory cytokines, such as TNF-α and IL-6, in response to microbial stimuli. This regulation of cytokine production helps balance immune responses and prevents excessive inflammatory reactions that could lead to tissue damage or autoimmune conditions.

Regulation of Innate Immune Responses:

• Through its effects on ROS production, phagocytosis, and cytokine secretion, SLAMF8 contributes to the modulation of innate immune responses, acting as a checkpoint for inflammatory regulation. By influencing innate immune cell activity, SLAMF8 has a broader impact on the immune response, providing signals that determine the extent and duration of inflammatory reactions.

Influence on Disease Susceptibility:

• SLAMF8’s role in ROS regulation and cytokine production positions it as a key player in determining susceptibility to infections, especially bacterial infections. By enhancing or inhibiting ROS production and phagocytic activity, SLAMF8 contributes to the body's ability to control pathogen spread, especially in tissues exposed to microbial invasion.

Clinical Issues

Autoimmune and Inflammatory Disorders:

• Dysregulation of SLAMF8 signaling has been implicated in autoimmune and inflammatory diseases. Due to its role in regulating cytokine production and ROS, altered SLAMF8 function may lead to either excessive inflammation or insufficient immune response. For example, overactivation of SLAMF8-related pathways could contribute to chronic inflammatory diseases, whereas insufficient activity might impair effective immune defense against pathogens.

Infectious Diseases:

• Given SLAMF8’s function in regulating ROS production and cytokine release, it has been studied in the context of infectious diseases. In bacterial infections, effective SLAMF8 function supports immune clearance of pathogens by enhancing ROS and phagocytic activity in macrophages and neutrophils. However, if dysregulated, SLAMF8 function can lead to inadequate pathogen clearance or exaggerated inflammation, both of which are detrimental to health.
• Further studies are exploring SLAMF8’s potential as a therapeutic target to enhance or suppress immune responses during infections, depending on the nature of the pathogen and the immune response required.

Cancer:

• SLAMF8’s modulation of ROS and inflammatory responses positions it as a potential factor in the tumor microenvironment, where inflammation and immune cell function are critical in cancer development and progression. Abnormal expression of SLAMF8 in immune cells within the tumor microenvironment might alter immune surveillance or immune cell behavior, potentially influencing tumor progression.

Summary

SLAMF8 is a member of the SLAM family, which is involved in immune cell regulation and communication. Uniquely among SLAM receptors, SLAMF8 does not rely on the SAP signaling pathway and instead utilizes alternative intracellular signaling adaptors to exert its effects, particularly in macrophages, neutrophils, and dendritic cells. SLAMF8's extracellular Ig-like domain enables it to mediate immune cell interactions, while its intracellular domain allows for non-SAP-dependent signaling, distinguishing it from other SLAM family members.

Functionally, SLAMF8 modulates reactive oxygen species production, phagocytosis, and cytokine production in response to microbial and inflammatory stimuli. This receptor plays a critical role in regulating innate immune responses, particularly those involving macrophages and neutrophils. By controlling ROS production and cytokine release, SLAMF8 helps balance the immune response, preventing both under-activation and over-activation that could lead to infection susceptibility or excessive inflammation, respectively.

Clinically, SLAMF8 has implications in autoimmune diseases, infectious diseases, and potentially in cancer, where its function in immune regulation may influence disease progression or immune response efficacy. Due to its central role in modulating inflammatory and immune processes, SLAMF8 continues to be a focus of research as a potential therapeutic target for modulating immune responses in various disease contexts.