KIR2DL3 - Killer cell immunoglobulin-like receptor 2DL3 |Elisa - Clia - Antibody - Protein

Background

KIR2DL3 is an inhibitory receptor that is part of the killer cell immunoglobulin-like receptor (KIR) family, which is primarily expressed on natural killer (NK) cells and some T-cell subsets. This receptor plays a pivotal role in immune surveillance and modulation by binding to specific HLA class I molecules, particularly HLA-C alleles, on potential target cells. KIR2DL3 recognizes HLA-C1 (characterized by an asparagine at position 80), which is different from HLA-C2 (lysine at position 80) recognized by related receptors like KIR2DL1. By binding to HLA-C1, KIR2DL3 sends inhibitory signals that regulate NK cell cytotoxicity, promoting immune tolerance and minimizing the risk of autoimmunity.

The KIR genes, including KIR2DL3, are located on chromosome 19q13.4 in a highly polymorphic region known as the leukocyte receptor complex (LRC). Genetic variability within this complex, particularly in the KIR2DL3 and its HLA-C ligands, contributes to diversity in immune response among individuals. Variants in KIR2DL3 and other KIR genes are associated with differential susceptibility to diseases, including autoimmune disorders, viral infections, and cancers.

Protein Structure

The structure of KIR2DL3 consists of three main regions: the extracellular domain, the transmembrane domain, and the cytoplasmic tail.

Extracellular Domain:

• KIR2DL3 has two extracellular immunoglobulin-like domains, referred to as D1 and D2. These domains mediate binding to HLA-C1 molecules on the surface of target cells.
• The D1 and D2 domains each contain loops with specific amino acids that enable selective binding to HLA-C1 over other HLA alleles. Variations within these domains contribute to the specificity and affinity of the receptor for different HLA-C molecules.
• These extracellular domains are glycosylated, which aids in protein stability and enhances ligand binding. This glycosylation occurs at conserved sites within the D1 and D2 domains.

Transmembrane Domain:

• The single transmembrane domain anchors KIR2DL3 within the NK cell membrane, facilitating stable interactions with target cell ligands.
• Although the transmembrane region does not participate directly in ligand binding, it ensures the correct orientation and positioning of KIR2DL3 on the NK cell surface, optimizing ligand-receptor interaction.

Cytoplasmic Tail:

• KIR2DL3 has a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon binding with an HLA-C ligand, these ITIMs are phosphorylated, leading to recruitment of phosphatases such as SHP-1 and SHP-2.
• SHP-1 and SHP-2 phosphatases dephosphorylate key signaling molecules within the NK cell, initiating a cascade that ultimately suppresses NK cell activation. This inhibitory signaling pathway is critical for preventing NK cells from attacking healthy cells that express appropriate HLA-C ligands.

This structural configuration allows KIR2DL3 to perform its primary function—distinguishing between healthy cells that display self-HLA markers and abnormal cells that lack these markers. The specificity for HLA-C1 is mediated by key residues within the D1 and D2 domains, which vary slightly among KIR family members, affecting their binding properties and functional effects.

Classification and Subtypes

KIR2DL3 belongs to the KIR family, which includes receptors with either two or three extracellular immunoglobulin-like domains (2D or 3D) and either long or short cytoplasmic tails (L or S). The “2DL” designation of KIR2DL3 indicates that it has two extracellular domains and a long cytoplasmic tail with inhibitory ITIMs.

KIR2DL3 is part of a subgroup within the KIR family that specifically binds to HLA-C molecules, distinguishing it from other KIR receptors that may recognize HLA-A or HLA-B alleles. It is closely related to KIR2DL1 and KIR2DL2, which also bind HLA-C but show differences in ligand preference (HLA-C1 for KIR2DL3 and KIR2DL2, HLA-C2 for KIR2DL1). These related receptors share structural similarities but differ in ligand specificity and signal strength, contributing to functional diversity in NK cell responses.

Function and Biological Significance

KIR2DL3 is critical for immune regulation and self-tolerance. Its functions and significance are described as follows:

Inhibition of NK Cell Activation:

• When KIR2DL3 binds HLA-C1 on a target cell, the receptor’s ITIMs are phosphorylated, initiating an inhibitory signaling cascade that dampens NK cell cytotoxic responses. This mechanism prevents NK cells from attacking cells expressing self-HLA-C1 molecules, supporting immune self-tolerance.
• Inhibitory signaling through KIR2DL3 reduces the release of cytotoxic granules and pro-inflammatory cytokines, thereby preventing unintended damage to healthy cells and maintaining immune homeostasis.

Role in Immune Surveillance:

• KIR2DL3 enables NK cells to detect cells with altered HLA-C expression, which can occur in infected or transformed cells. Cells that downregulate HLA-C, such as certain cancer cells or cells infected with viruses, fail to inhibit NK cells via KIR2DL3, allowing NK cell activation and targeted cytotoxicity.
• This “missing-self” recognition mechanism helps NK cells eliminate potentially harmful cells while sparing healthy cells that exhibit normal HLA expression.

Reproductive Immunology:

• KIR2DL3 has been implicated in reproductive immune tolerance, particularly in interactions at the maternal-fetal interface. Interactions between KIR2DL3 on maternal NK cells and HLA-C1 on fetal trophoblasts contribute to placental development and are thought to influence pregnancy outcomes.
• Specific KIR2DL3-HLA combinations may impact the risk of pregnancy complications, such as preeclampsia and fetal growth restriction, although the exact mechanisms remain under investigation.

Clinical Issues

Autoimmune Diseases:

• Genetic variability in KIR2DL3 and its HLA-C ligands has been linked to autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. Certain KIR-HLA combinations may predispose individuals to altered NK cell function and immune dysregulation, contributing to autoimmunity.
• The presence or absence of KIR2DL3-HLA interactions can influence disease susceptibility and progression in autoimmune conditions, although the exact contributions are complex and multifactorial.

Cancer:

• In the context of cancer, KIR2DL3’s interaction with HLA-C1 can be exploited by tumor cells to evade NK cell detection. Tumors that express HLA-C1 may engage KIR2DL3 and inhibit NK cell activity, promoting immune escape.
• Blocking KIR2DL3-HLA interactions is a potential strategy in cancer immunotherapy, aiming to release NK cells from inhibition and enhance their cytotoxicity against tumor cells.

Transplantation:

• KIR2DL3 is significant in hematopoietic stem cell transplantation (HSCT), where KIR-HLA compatibility between donor and recipient can affect transplant outcomes. Donor KIR2DL3 interactions with recipient HLA-C1 may modulate graft-versus-leukemia (GVL) effects, reducing relapse risk while minimizing graft-versus-host disease (GVHD).
• Certain KIR-HLA combinations may be favorable for improved immune reconstitution and protection against infections post-transplant.

Infectious Diseases:

• The interaction between KIR2DL3 and HLA-C1 affects susceptibility to certain infectious diseases. Viral infections, such as those caused by cytomegalovirus (CMV) and hepatitis C virus (HCV), may alter HLA-C expression, impacting KIR2DL3-mediated NK cell responses.
• Variability in KIR2DL3-HLA-C genotypes has been associated with differences in infection outcomes, with some alleles linked to increased immune response against certain pathogens.

Summary

KIR2DL3 is an inhibitory receptor in the KIR family, recognizing HLA-C1 molecules on target cells and regulating NK cell activation through its ITIM-containing cytoplasmic tail. This receptor plays a vital role in immune regulation, self-tolerance, and immune surveillance, allowing NK cells to differentiate between healthy and abnormal cells. Structurally, KIR2DL3 contains two extracellular immunoglobulin-like domains that bind HLA-C1, a transmembrane domain, and a long cytoplasmic tail essential for inhibitory signaling. Clinical implications of KIR2DL3 include its involvement in autoimmune diseases, cancer immune evasion, transplantation outcomes, and responses to infectious diseases. Therapeutic approaches targeting KIR2DL3 and its interactions with HLA-C1 are being explored, particularly in cancer and transplantation immunology, to modulate NK cell activity and enhance immune response against malignant or infected cells.