KIR2DL5A - Killer cell immunoglobulin-like receptor 2DL5A |Elisa - Clia - Antibody - Protein

Background

Killer cell immunoglobulin-like receptor 2DL5A (KIR2DL5A) is a member of the KIR family, which plays a crucial role in immune regulation, especially in natural killer (NK) cell and some T-cell activities. These receptors allow immune cells to differentiate between normal cells and those that may be infected, stressed, or malignant. KIR2DL5A, like other inhibitory KIR receptors, is known for its role in maintaining immune tolerance by providing inhibitory signals to prevent NK cells from attacking healthy tissues. This regulation is achieved through interactions with specific ligands, mainly human leukocyte antigen (HLA) class I molecules on target cells. However, the specific HLA ligands for KIR2DL5A remain under research, with some studies suggesting unique ligand interactions within this receptor subtype.

KIR2DL5A is located on chromosome 19 within the KIR gene cluster, which exhibits considerable genetic diversity across individuals. This diversity allows NK cells to adapt to various pathogenic and environmental pressures. The polymorphic nature of KIR genes like KIR2DL5A contributes to variations in immune responses between individuals, which can influence susceptibility to infections, autoimmune diseases, and cancer.

Protein Structure

KIR2DL5A exhibits a structure typical of KIR family inhibitory receptors, featuring distinct regions that enable its specific ligand-binding and signaling functions:

Extracellular Domains:

• KIR2DL5A has two extracellular immunoglobulin-like domains, denoted as D0 and D2. These domains are responsible for the receptor's binding to specific ligands, although, unlike other KIRs, the specific HLA class I ligand for KIR2DL5A is not fully established.
• The D0 and D2 domains consist of a typical Ig-like fold with beta-sheets and a highly conserved cysteine bridge that stabilizes the domain.
• Critical amino acid residues within these domains contribute to the structural integrity required for interaction with target molecules on opposing cells.

Transmembrane Domain:

• KIR2DL5A has a transmembrane domain that anchors it to the NK cell membrane. This hydrophobic region enables receptor stability and proximity to potential interacting partners on the cell membrane.
• Unlike activating KIR receptors, which have a charged residue in the transmembrane region to bind adaptor proteins, KIR2DL5A lacks such a charge, aligning it with inhibitory receptors that do not recruit activating signaling molecules.

Cytoplasmic Tail:

• The cytoplasmic domain of KIR2DL5A is characterized by a long tail that contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs).
• These ITIM motifs are essential for downstream inhibitory signaling. Upon ligand engagement, tyrosine residues within the ITIMs are phosphorylated, enabling the recruitment of SH2 domain-containing phosphatases, such as SHP-1 and SHP-2.
• The ITIM-mediated signaling cascade ultimately leads to inhibition of NK cell activation, reducing cytotoxic activity and cytokine production.

Classification and Subtypes

KIR2DL5A is classified within the KIR family based on its two immunoglobulin-like domains and inhibitory function, represented by the "2DL" designation. This family includes other receptors with varied combinations of domains and signaling functions. KIR2DL5 has two main isoforms, KIR2DL5A and KIR2DL5B, generated through gene duplication events:

KIR2DL5A:

• Located on chromosome 19q13.4, KIR2DL5A is the focus of immune research due to its distinct regulatory roles and expression patterns on NK and T cells.
• KIR2DL5A expression is also unique among KIR receptors due to allele-specific expression patterns, where only one allele in an individual may be expressed.

KIR2DL5B:

• Another closely related isoform, KIR2DL5B, shares a high degree of similarity with KIR2DL5A but differs in expression patterns and possibly ligand specificity.
• This duplication provides further variability within the immune responses among different individuals.

Function and Biological Significance

KIR2DL5A’s primary role, like other inhibitory KIR receptors, is in modulating NK cell responses through inhibitory signaling. The receptor achieves this by binding specific ligands (likely HLA class I molecules, although the precise ligand remains under investigation), which allows NK cells to recognize self and differentiate it from potentially harmful cells.

Immune Modulation:

• By inhibiting NK cell activity upon engagement, KIR2DL5A plays a role in immune tolerance, helping prevent inappropriate immune responses against healthy tissues.
• The specificity of KIR2DL5A for its yet-to-be-identified HLA ligands allows NK cells to avoid attacking cells expressing these ligands, ensuring that immune reactions are directed only towards stressed, infected, or malignant cells lacking sufficient inhibitory signals.

Antiviral Response:

• Similar to other KIRs, KIR2DL5A likely contributes to the body’s antiviral defenses. Viruses often evade immune detection by downregulating MHC class I molecules, thereby avoiding detection by T-cells but rendering them susceptible to NK cell-mediated killing.
• KIR2DL5A may modulate these responses by detecting the absence of its specific ligand on infected cells, thereby allowing NK cell activation in the context of viral infections.

Cancer Surveillance:

• The inhibitory function of KIR2DL5A can play a role in cancer immunology. Tumor cells may exploit KIR signaling to evade immune detection by maintaining or upregulating HLA class I molecules to inhibit NK cell activity through KIR receptors, including KIR2DL5A.
• Research on KIR-blocking therapies aims to disrupt these inhibitory signals, reactivating NK cells’ ability to target cancer cells that would otherwise be protected by KIR-mediated inhibition.

Clinical Issues

The clinical significance of KIR2DL5A relates to its role in immunity and the genetic diversity of KIR expression. Variants in KIR2DL5A can impact individual susceptibility to autoimmune diseases, infections, and cancer.

Autoimmune Diseases:

• Dysregulated KIR2DL5A expression or function may contribute to autoimmune diseases by altering NK cell tolerance to self-tissues. Aberrant expression of KIR2DL5A or shifts in ligand availability may trigger inappropriate NK cell responses.
• Certain polymorphisms within KIR2DL5A are associated with increased susceptibility to autoimmune diseases like rheumatoid arthritis and multiple sclerosis.

Infectious Diseases:

• Polymorphisms in KIR genes, including KIR2DL5A, are associated with different outcomes in infectious diseases. Variations in KIR2DL5A expression or function can impact NK cell responses to viral infections by altering the balance between inhibitory and activating signals.
• Studies have shown that specific KIR and HLA combinations may provide protective effects or predispose individuals to particular infectious diseases.

Cancer:

• Tumor cells often exploit KIR-mediated inhibition to avoid NK cell-mediated destruction. Some tumors express high levels of HLA molecules to engage inhibitory receptors like KIR2DL5A, thereby protecting themselves from immune attack.
• Research on anti-KIR antibodies is ongoing, aiming to block KIR-mediated inhibition and re-enable NK cells to target tumor cells. KIR2DL5A’s involvement in immune evasion mechanisms makes it a candidate target in cancer immunotherapy.

Summary

KIR2DL5A is a crucial inhibitory receptor in the KIR family, expressed mainly on NK cells, where it modulates immune responses through interactions with HLA class I molecules. Structurally, KIR2DL5A is characterized by its two extracellular immunoglobulin-like domains, a hydrophobic transmembrane domain, and a cytoplasmic tail containing ITIM motifs responsible for inhibitory signaling. The receptor, along with its isoform KIR2DL5B, plays a vital role in distinguishing healthy cells from abnormal ones, thereby contributing to immune homeostasis and self-tolerance.

KIR2DL5A's biological significance is highlighted in its roles in immune regulation, antiviral defense, and cancer surveillance. Clinically, variations in KIR2DL5A expression and polymorphisms influence individual susceptibility to autoimmune diseases, infections, and cancer. Ongoing research focuses on targeting KIR2DL5A to enhance NK cell responses, providing potential therapeutic avenues in immunotherapy. Understanding the functions and regulation of KIR2DL5A aids in developing effective treatments for immune-related diseases and cancer, emphasizing its importance in the immune regulatory network.