KIR2DS4 - Killer cell immunoglobulin-like receptor 2DS4 |Elisa - Clia - Antibody - Protein

Background

Killer cell immunoglobulin-like receptor 2DS4 (KIR2DS4) is part of the Killer-cell Immunoglobulin-like Receptor (KIR) family, which plays a central role in the immune system, specifically in regulating natural killer (NK) cells and certain T-cell functions. KIR2DS4 is one of the activating receptors in the KIR family and is particularly involved in identifying cells that may be infected, stressed, or tumorigenic. KIR receptors, including KIR2DS4, contribute to the immune system's adaptability through interactions with human leukocyte antigen (HLA) molecules, typically class I. However, unlike many KIR receptors that mediate inhibitory signals, KIR2DS4 is an activating receptor. It provides stimulatory signals that help NK cells become cytotoxic toward specific target cells.

KIR genes, including KIR2DS4, are highly polymorphic, with substantial genetic variation between individuals, contributing to variations in immune response. KIR genes are clustered on chromosome 19, and their expression varies across different populations, impacting immune response diversity. This variation has implications for disease susceptibility, transplantation compatibility, and response to certain therapies.

Protein Structure

KIR2DS4 exhibits a characteristic structure, typical of activating KIR family receptors, with specific regions responsible for ligand binding and signal transduction:

Extracellular Domains:

• KIR2DS4 has two immunoglobulin-like extracellular domains, known as D0 and D2, which are crucial for binding to target molecules, primarily certain HLA class I ligands. These domains adopt a beta-sheet structure that provides a surface for interaction with HLA molecules.
• Within these domains, KIR2DS4 shares structural homology with other KIR receptors, containing conserved cysteine residues that stabilize each domain through disulfide bonds.
• Certain polymorphisms in the D0 and D2 domains impact binding affinity and specificity for HLA ligands, influencing the receptor's functionality.

Transmembrane Domain:

• The transmembrane region of KIR2DS4 is a hydrophobic segment anchoring the receptor to the cell membrane. Unlike inhibitory KIR receptors, which typically have a neutral transmembrane region, KIR2DS4 has a positively charged lysine residue in this domain.
• This lysine residue enables KIR2DS4 to associate with the DNAX-activating protein of 12 kDa (DAP12), an adaptor molecule essential for activating signal transduction.

Cytoplasmic Tail:

• KIR2DS4 has a short cytoplasmic tail that lacks immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are present in inhibitory KIR receptors. Instead, the receptor relies on the DAP12 adaptor protein to initiate downstream signaling.
• Upon ligand binding, the association with DAP12 facilitates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on DAP12, triggering a cascade that activates NK cell cytotoxic functions.

Classification and Subtypes

KIR2DS4 is classified as an activating receptor within the KIR family. While KIRs are generally grouped by their domain structures and functional properties (inhibitory or activating), KIR2DS4 falls into the 2D category, characterized by having two Ig-like domains (D0 and D2) and an activating function.

KIR2DS4 has notable polymorphisms and isoforms:

Functional KIR2DS4:

• The fully functional KIR2DS4 isoform, known as the “full-length” variant, binds specific HLA class I molecules and transmits activating signals through DAP12.

KIR2DS4*003 and Related Variants:

• Many individuals carry a variant of KIR2DS4 that contains a 22-base-pair deletion, producing a truncated protein that is not expressed on the cell surface and, therefore, non-functional in terms of immune activation.
• These non-functional variants are common in the human population and may influence susceptibility to disease by impacting the overall balance of activating and inhibitory KIR receptors.

Function and Biological Significance

The primary function of KIR2DS4 is to stimulate NK cell activation in response to certain target cells. Its role in immune regulation and surveillance is significant for detecting and eliminating cells that may lack adequate HLA class I expression, often a characteristic of infected or transformed cells.

NK Cell Activation:

• KIR2DS4 engages with specific HLA-C alleles and other ligands, promoting NK cell cytotoxicity against cells that present these ligands in low or altered forms.
• Upon engagement, KIR2DS4, through DAP12, initiates signaling that leads to the activation of downstream kinases, such as Syk and Zap-70, which in turn activate pathways responsible for cytokine production and the release of cytotoxic granules.

Immune Surveillance:

• The presence of KIR2DS4 enables NK cells to recognize and respond to cellular stress or malignancy. Cells that evade T-cell detection by downregulating HLA molecules are often targets for NK cells, making KIR2DS4 an essential component of tumor and infection surveillance.

Cross-talk with Other Receptors:

• KIR2DS4 functions alongside both activating and inhibitory KIR receptors. The balance between signals from KIR2DS4 and inhibitory receptors determines the NK cell response, helping prevent unintended cell killing and promoting immune tolerance.

Clinical Issues

KIR2DS4 has clinical significance in a variety of diseases and immune-related conditions, and its polymorphisms can impact disease susceptibility, outcomes in transplantation, and immune responses.

Infectious Diseases:

• Variants of KIR2DS4 have been associated with differential susceptibility to infectious diseases. For example, individuals carrying functional KIR2DS4 have been found to have an enhanced immune response against viral infections, including HIV.
• KIR2DS4 variants may alter NK cell responses to pathogens, impacting the severity and progression of infections.

Cancer:

• KIR2DS4, by mediating NK cell responses against tumor cells with altered HLA expression, contributes to immune surveillance against cancer.
• Variants of KIR2DS4 that lack functionality may reduce NK cell efficacy in targeting tumor cells, potentially influencing cancer susceptibility or progression.
• Emerging therapies aim to enhance KIR2DS4-mediated activation in cancer patients, promoting NK cell anti-tumor responses as part of immunotherapy.

Autoimmune Diseases:

• In autoimmune diseases, such as rheumatoid arthritis and type 1 diabetes, specific KIR2DS4 polymorphisms are associated with either increased risk or protection. The balance of activating and inhibitory KIR receptors, including KIR2DS4, affects immune tolerance mechanisms, possibly contributing to autoimmunity in genetically susceptible individuals.

Transplantation:

• In hematopoietic stem cell transplantation, the compatibility of KIR genes, including KIR2DS4, influences outcomes such as graft-versus-host disease (GVHD) and graft-versus-leukemia effects.
• Transplant patients with donor cells expressing activating KIR genes like KIR2DS4 have shown better control over residual cancer cells, suggesting that KIR2DS4 compatibility can be beneficial in preventing cancer relapse.

Summary

KIR2DS4 is a key activating receptor within the KIR family, crucial to immune surveillance and NK cell activation. The receptor has a characteristic structure featuring two immunoglobulin-like extracellular domains (D0 and D2), a charged transmembrane region for DAP12 association, and a short cytoplasmic tail. Its primary function is to detect and initiate immune responses against cells with low HLA class I expression, common in infections and malignancies.

KIR2DS4 variants exhibit genetic diversity, with functional and non-functional isoforms influencing individual immune responses. This variability impacts susceptibility to infections, autoimmune conditions, cancer, and transplantation outcomes. Functional KIR2DS4 enhances NK cell cytotoxicity, while truncated variants lack cell-surface expression, reducing NK cell activation. Clinically, understanding KIR2DS4's role in immunity provides insights into potential therapeutic approaches, particularly in infectious disease, cancer, and transplantation settings.