KIR2DL2 - Killer cell immunoglobulin-like receptor 2DL2 |Elisa - Clia - Antibody - Protein

Background

Killer cell immunoglobulin-like receptors (KIRs) are a family of proteins primarily expressed on the surface of natural killer (NK) cells and some T-cell subsets. KIR2DL2, a member of this family, plays an essential role in regulating NK cell function and contributes to immune surveillance and self-tolerance mechanisms. KIR2DL2 is an inhibitory receptor that recognizes specific human leukocyte antigen (HLA) class I molecules on target cells, allowing NK cells to modulate their activity in response to changes in HLA expression, which often occur in cells affected by infection, cancer, or other pathological states. KIR2DL2’s primary role is to suppress NK cell activity upon binding to its specific HLA ligand, which reduces the likelihood of NK cell-mediated destruction of healthy cells displaying self-HLA markers.

The genes encoding KIR proteins, including KIR2DL2, are located on chromosome 19q13.4 within the leukocyte receptor complex (LRC). KIR genes are highly polymorphic, with significant inter-individual variability in gene content and sequence. This variability contributes to an individual’s unique immune response capacity, as well as to population-level diversity in immune defense. The primary ligand for KIR2DL2 is HLA-C, specifically the HLA-C1 epitope (characterized by the presence of asparagine at position 80), which is distinct from the HLA-C2 epitope (lysine at position 80) recognized by other KIR molecules like KIR2DL1.

Protein Structure

KIR2DL2 is a type I transmembrane glycoprotein, comprising three main regions: the extracellular domain, the transmembrane domain, and the cytoplasmic tail.

Extracellular Domain:

• The extracellular domain of KIR2DL2 includes two immunoglobulin-like domains, known as D1 and D2, connected by a short stalk. These domains are responsible for binding to the HLA-C1 ligand on target cells.
• The D1 and D2 domains exhibit structural variation that contributes to the receptor’s specificity for HLA-C alleles. This region is also glycosylated, which enhances receptor stability and ligand-binding capability.
• These immunoglobulin-like domains have highly conserved regions that determine ligand specificity, but the loops at the binding site can vary, affecting how tightly KIR2DL2 binds to different HLA-C molecules.

Transmembrane Domain:

• KIR2DL2’s single-pass transmembrane domain anchors it within the cell membrane, providing a stable interface for interactions with HLA-C molecules on neighboring cells.
• While the transmembrane region is not directly involved in ligand binding, it ensures that KIR2DL2 is correctly positioned to interact with its ligands on the cell surface.

Cytoplasmic Tail:

• The cytoplasmic tail of KIR2DL2 is essential for signaling and contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon ligand engagement, these ITIMs become phosphorylated and recruit phosphatases, particularly SHP-1 and SHP-2.
• The recruitment of these phosphatases initiates a signaling cascade that results in the inhibition of NK cell activation. This inhibitory signaling prevents the NK cell from releasing cytotoxic granules or cytokines, thereby preventing unintended damage to healthy cells.

The structural configuration of KIR2DL2 facilitates its ability to recognize and bind HLA-C1, and its cytoplasmic ITIM domains are critical for transmitting inhibitory signals within NK cells.

Classification and Subtypes

KIR2DL2 is part of the KIR family, classified based on its extracellular domains and cytoplasmic tail structure. Specifically, “2DL” refers to KIR proteins with two extracellular immunoglobulin-like domains (D1 and D2) and a long cytoplasmic tail with inhibitory function. KIR2DL2 is often grouped with other inhibitory KIRs that recognize HLA-C molecules, such as KIR2DL1 and KIR2DL3, though they differ in HLA specificity and affinity.

KIR genes exhibit a high degree of polymorphism, contributing to substantial inter-individual variability. KIR2DL2 and KIR2DL3 are highly similar and often considered allelic variants, differing in their affinity for certain HLA-C1 alleles. These polymorphisms affect KIR2DL2’s binding affinity and inhibitory strength, impacting the strength of the immune response.

Function and Biological Significance

KIR2DL2 is critical for immune regulation, self-tolerance, and NK cell-mediated surveillance in the following ways:

Inhibitory Regulation of NK Cells:

• KIR2DL2 binds to HLA-C1 molecules on potential target cells, transmitting inhibitory signals that prevent NK cell activation. This interaction is essential for maintaining self-tolerance by ensuring that NK cells do not attack cells expressing normal levels of self-HLA class I molecules.
• The inhibitory signal from KIR2DL2 suppresses NK cell cytotoxic responses, including the release of perforin and granzymes and the secretion of pro-inflammatory cytokines. This suppression prevents unnecessary tissue damage and contributes to the homeostasis of the immune system.

Role in Immune Surveillance:

• KIR2DL2 allows NK cells to detect cells with altered HLA expression, which is often seen in tumor cells or cells infected by certain viruses. Some pathogens and cancers downregulate HLA expression to evade immune detection by T cells, potentially leaving them vulnerable to NK cell responses.
• In situations where HLA-C is downregulated or absent, KIR2DL2 inhibition is reduced, allowing NK cells to become activated and target such cells for destruction. This “missing-self” mechanism enables NK cells to eliminate transformed or infected cells while sparing healthy cells.

Reproductive Immunology:

• KIR2DL2 is also involved in immune interactions at the maternal-fetal interface, where interactions between maternal KIR receptors and fetal HLA-C molecules on trophoblast cells play a role in placental development. Specific KIR-HLA combinations may influence pregnancy outcomes, potentially affecting placental growth and the risk of complications like preeclampsia.

Clinical Issues

Autoimmune Diseases:

• Variability in KIR2DL2 and its interaction with HLA-C alleles has been associated with susceptibility to autoimmune diseases. In some autoimmune conditions, such as rheumatoid arthritis and ankylosing spondylitis, certain KIR2DL2 and HLA-C genotypes may contribute to altered NK cell regulation, affecting immune tolerance and inflammatory responses.
• Genetic studies have shown correlations between KIR2DL2 and specific autoimmune disorders, although the precise mechanisms remain under investigation. It is thought that altered NK cell function due to specific KIR-HLA interactions may disrupt immune regulation in autoimmune settings.

Cancer:

• The interaction between KIR2DL2 and HLA-C is important in tumor immunology, as some cancers exploit this pathway to evade NK cell detection by upregulating HLA-C1 expression. By engaging KIR2DL2 and other inhibitory receptors, tumor cells can suppress NK cell activity, promoting immune evasion.
• Targeting KIR-HLA interactions is an area of interest for cancer immunotherapy, where blocking inhibitory signals to NK cells may enhance their ability to attack cancer cells. Antibodies that disrupt KIR2DL2-HLA interactions could potentially enhance NK cell cytotoxicity against tumors.

Transplantation:

• KIR-HLA matching is a consideration in hematopoietic stem cell transplantation (HSCT), where NK cell activity can affect transplant outcomes. KIR2DL2 compatibility with donor or recipient HLA-C can impact graft-versus-leukemia effects and the risk of graft-versus-host disease.
• KIR2DL2-HLA mismatches may enhance NK cell activity against leukemia cells in some transplant settings, potentially improving outcomes in patients with hematologic cancers.

Infectious Diseases:

• The interaction of KIR2DL2 with HLA-C can also impact susceptibility to infectious diseases. Certain viruses, such as cytomegalovirus (CMV), are known to modulate HLA expression to evade immune responses. The presence of KIR2DL2-HLA interactions can influence NK cell responses to such pathogens, impacting viral clearance.
• Polymorphisms in KIR2DL2 and HLA-C alleles have been associated with differences in susceptibility and immune response to infections, including CMV and HIV.

Summary

KIR2DL2 is an inhibitory receptor expressed on NK cells, where it plays a central role in immune regulation by recognizing HLA-C1 molecules. Structurally, KIR2DL2 includes two immunoglobulin-like extracellular domains for HLA binding, a transmembrane domain, and a cytoplasmic tail containing ITIMs that mediate inhibitory signaling. This receptor’s primary function is to suppress NK cell activation, ensuring self-tolerance and preventing unnecessary immune responses against healthy cells expressing self-HLA class I molecules. The clinical relevance of KIR2DL2 spans autoimmune diseases, cancer, transplantation, and infectious disease contexts, where the receptor’s interaction with HLA-C can influence immune response and disease susceptibility. Therapeutic strategies targeting KIR2DL2-HLA interactions offer potential in treating cancers, modulating immune responses, and improving transplant outcomes.