KIR2DL4 - Killer cell immunoglobulin-like receptor 2DL4 |Elisa - Clia - Antibody - Protein

Background

KIR2DL4 is a member of the killer cell immunoglobulin-like receptor (KIR) family, which plays an essential role in immune regulation, particularly through the modulation of natural killer (NK) cell activity. KIR2DL4 is unique among KIRs in its ability to transduce both activating and inhibitory signals, allowing it to play a nuanced role in immune responses. Unlike most KIRs, which are specific to either HLA-A, -B, or -C, KIR2DL4 binds specifically to HLA-G, a non-classical MHC class I molecule. HLA-G is primarily expressed in tissues with immune privilege, such as the placenta, where it contributes to immune tolerance, thus implicating KIR2DL4 in maternal-fetal immune interactions.

The gene encoding KIR2DL4 is located on chromosome 19q13.4, within the leukocyte receptor complex (LRC), alongside other KIR genes. The KIR family is highly polymorphic, resulting in a wide array of receptor-ligand combinations that contribute to individual variations in immune responses. KIR2DL4’s interaction with HLA-G is particularly important for its role in promoting tolerance in pregnancy and its potential involvement in immune responses to certain infections and cancers.

Protein Structure

The protein structure of KIR2DL4 is distinctive among KIR family members, with notable features that support its dual signaling functions.

Extracellular Domain:

• KIR2DL4 contains two immunoglobulin-like extracellular domains, D0 and D2, which allow it to bind to HLA-G on target cells.
• Unlike other KIR receptors that typically contain D1 and D2 domains, KIR2DL4’s extracellular structure lacks a D1 domain. The D0-D2 domain structure is crucial for binding the distinct HLA-G ligand, distinguishing KIR2DL4’s interaction profile from other KIR receptors.
• The D0 domain contains key amino acid residues that mediate binding to the α3 domain of HLA-G, as well as β2-microglobulin, which associates with HLA-G.

Transmembrane Domain:

• KIR2DL4 has a unique transmembrane region that includes a positively charged arginine residue. This arginine residue is atypical among inhibitory KIRs and is essential for KIR2DL4’s ability to initiate activating signaling.
• This positively charged residue in the transmembrane domain facilitates association with FcεRIγ, an adaptor protein that mediates activation signals. This feature is crucial to KIR2DL4’s function as it enables the receptor to engage in both inhibitory and activating signaling pathways.

Cytoplasmic Tail:

• The cytoplasmic tail of KIR2DL4 contains a single immunoreceptor tyrosine-based inhibitory motif (ITIM), typically associated with inhibitory signaling in NK cells. This ITIM motif enables KIR2DL4 to recruit SHP-1 and SHP-2 phosphatases, which can dampen cell activation.
• However, KIR2DL4 lacks multiple ITIMs present in other inhibitory KIRs, reflecting its unique ability to balance inhibitory and activating signals.
• The ITIM domain allows KIR2DL4 to participate in inhibition, though in certain contexts, the receptor can also trigger activation, particularly in response to ligand binding in endosomal compartments.

This structure supports KIR2DL4’s dual functionality, whereby the receptor can generate both activating and inhibitory responses in NK cells. The interaction with HLA-G is also mediated by the receptor's ability to undergo endocytosis, where signaling predominantly occurs.

Classification and Subtypes

KIR2DL4 belongs to the KIR family, characterized by immunoglobulin-like receptors with either two or three extracellular domains (2D or 3D) and long or short cytoplasmic tails (L or S). Specifically, KIR2DL4 is classified based on:

• Immunoglobulin-Like Domains: It possesses two domains (D0 and D2), setting it apart from other KIRs with the typical D1-D2 configuration.
• Cytoplasmic Tail: The long tail, with an ITIM motif, allows inhibitory signaling, but it lacks multiple ITIM motifs seen in other inhibitory KIRs.
• Transmembrane Charge: The positively charged arginine in the transmembrane domain enables activation potential through adaptor proteins.

KIR2DL4 is unique in the KIR family as it has no close subtypes or variants that mirror its dual function and specific HLA-G binding capacity.

Function and Biological Significance

NK Cell Activation and Inhibition:

• When bound to HLA-G, KIR2DL4 can transduce signals that modulate NK cell function. This dual signaling allows NK cells to remain in a “poised” state where they can either activate or inhibit based on contextual cues.
• KIR2DL4’s activating function is initiated when it signals through FcεRIγ, particularly when HLA-G binding occurs in endosomes. This signaling can lead to the release of cytokines such as IFN-γ, which plays a role in immune modulation and inflammatory responses.

Maternal-Fetal Immune Tolerance:

• The interaction between KIR2DL4 and HLA-G is particularly important in pregnancy, where it contributes to the establishment of immune tolerance to the semi-allogeneic fetus. By binding to HLA-G on placental trophoblasts, KIR2DL4 suppresses excessive NK cell cytotoxicity, facilitating placental development and fetal protection.
• Aberrant KIR2DL4-HLA-G signaling has been implicated in pregnancy complications such as preeclampsia and recurrent miscarriage, underlining the receptor’s role in reproductive immunology.

Immune Response to Cancer and Infections:

• Through its ability to mediate cytokine release, KIR2DL4 can enhance immune responses against certain pathogens and tumors. Increased expression of HLA-G in tumors can either activate NK cells or lead to immune evasion by co-opting KIR2DL4’s inhibitory function.
• In cancer, the balance of KIR2DL4 signaling may determine whether NK cells are suppressed or activated, impacting tumor immunity. Targeting KIR2DL4 pathways has shown potential as a therapeutic approach to enhance NK cell activity in tumors expressing HLA-G.

Clinical Issues

Pregnancy Complications:

• Dysregulation in KIR2DL4-HLA-G interactions is associated with pregnancy disorders, including preeclampsia and recurrent miscarriage. Certain polymorphisms in KIR2DL4 or altered HLA-G expression may disrupt immune tolerance, leading to adverse pregnancy outcomes.
• Studies indicate that variations in the KIR2DL4 receptor or its signaling pathway can influence maternal immune tolerance and potentially lead to inflammatory responses that harm placental function.

Cancer Immune Evasion:

• Many cancers upregulate HLA-G expression to exploit KIR2DL4’s inhibitory pathway, thus evading NK cell-mediated immune surveillance. Tumors that express HLA-G may engage KIR2DL4, inhibiting NK cell activity and facilitating tumor progression.
• Therapeutic strategies aimed at blocking KIR2DL4-HLA-G interactions are being explored to overcome immune suppression in HLA-G-positive tumors.

Viral Infections:

• In viral infections, KIR2DL4 expression and its interaction with HLA-G can modulate immune responses. Viral infections that impact HLA-G expression can influence NK cell activity through KIR2DL4, affecting the ability of NK cells to control infection.
• Chronic infections may lead to upregulation of HLA-G on infected cells, dampening NK cell responses via KIR2DL4 and facilitating viral persistence.

Summary

KIR2DL4 is a unique receptor in the KIR family, notable for its capacity to transduce both activating and inhibitory signals, depending on the context of its HLA-G ligand interaction. Structurally distinct from other KIRs, KIR2DL4’s configuration includes a D0-D2 extracellular domain structure, a transmembrane domain with a positively charged arginine, and a single ITIM motif on its cytoplasmic tail. These features allow it to mediate nuanced immune responses, particularly relevant in maternal-fetal tolerance, infection, and cancer immune evasion.

The dual signaling potential of KIR2DL4 positions it as a critical modulator of NK cell function in various physiological and pathological contexts. Clinically, dysregulation of KIR2DL4 activity has implications in pregnancy disorders, cancer, and chronic infections, and its unique interaction with HLA-G makes it a potential therapeutic target in conditions requiring modulation of NK cell activity.