KIR2DL1 - Killer cell immunoglobulin-like receptor 2DL1 |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, where they play a crucial role in the innate immune system. KIR2DL1, a member of this family, specifically recognizes certain human leukocyte antigen (HLA) class I molecules, allowing NK cells to monitor cellular health by detecting variations in HLA expression. KIR2DL1 is an inhibitory receptor, meaning that its engagement generally suppresses NK cell cytotoxic activity. The interaction between KIR2DL1 and HLA class I molecules is part of a broader system known as immune surveillance, where NK cells detect and respond to stress or infection signals on potential target cells, such as virally infected or transformed cells.

KIRs are highly polymorphic and exhibit considerable variability among individuals. This diversity contributes to the versatility of NK cell responses, enhancing the immune system's adaptability. The genes encoding KIR proteins, including KIR2DL1, are located on chromosome 19q13.4 in the leukocyte receptor complex (LRC). KIR2DL1 recognizes HLA-C molecules, specifically those with the C2 epitope (HLA-C group 2), which consists of specific amino acid sequences.

Protein Structure

The structure of KIR2DL1 is critical for its function as an inhibitory receptor. It is a type I transmembrane glycoprotein consisting of three main structural domains: the extracellular domain, the transmembrane domain, and the cytoplasmic tail.

Extracellular Domain:

• The extracellular domain comprises two immunoglobulin-like domains, denoted as D1 and D2, which are connected to each other and to the cell membrane by a short stalk region.
• These immunoglobulin domains facilitate binding to the HLA-C molecules on target cells. The D1 and D2 domains contain the specific binding sites that recognize and engage with the C2 epitope on HLA-C molecules.
• This region is highly variable among individuals, contributing to KIR2DL1’s specificity and affinity variations for different HLA-C alleles. Glycosylation of the extracellular domain is also essential for the stability and functional configuration of the receptor.

Transmembrane Domain:

• The single-pass transmembrane domain anchors KIR2DL1 in the NK cell membrane. This domain enables KIR2DL1 to localize within the NK cell plasma membrane while facilitating signal transduction.
• The transmembrane domain of KIR2DL1 is not directly involved in ligand binding but plays a role in positioning the receptor appropriately within the cell membrane.

Cytoplasmic Tail:

• The cytoplasmic tail is a critical region for signaling and contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon binding to HLA-C molecules, these ITIMs become phosphorylated and recruit phosphatases such as SHP-1 and SHP-2.
• The recruited phosphatases initiate a signaling cascade that ultimately inhibits NK cell activation, preventing the release of cytotoxic granules. This inhibitory signaling prevents NK cells from attacking healthy cells that express HLA-C ligands.

Classification and Subtypes

KIR2DL1 is part of the KIR family and belongs to the subgroup of inhibitory KIRs with two extracellular domains, termed "2DL" based on their structural composition. Within the KIR family, receptors are classified by the number of extracellular immunoglobulin-like domains (e.g., 2D for two domains) and by the length of their cytoplasmic tail (L for long, with inhibitory function, and S for short, often associated with activating function). Variants of KIR2DL1 exist, arising from genetic polymorphisms that lead to functional diversity in receptor affinity and specificity for different HLA-C molecules. These polymorphisms play a role in an individual’s immune response and can affect susceptibility to certain diseases.

Function and Biological Significance

KIR2DL1 is integral to NK cell regulation and immune surveillance, with primary functions including the regulation of NK cell activity, maintenance of self-tolerance, and modulation of immune responses in infections and cancer.

Inhibitory Role in NK Cells:

• KIR2DL1 acts as an inhibitory receptor by recognizing specific HLA-C ligands, thereby suppressing NK cell activation upon ligand binding. This inhibition is essential for self-tolerance, ensuring that NK cells do not attack normal, healthy cells that express self-HLA class I molecules.
• The interaction between KIR2DL1 and HLA-C2 molecules transmits inhibitory signals, preventing NK cells from attacking the cell displaying the ligand. This mechanism allows NK cells to distinguish between healthy and compromised cells, such as those that may be infected or transformed.

Immune Surveillance and Tumor Immunology:

• KIR2DL1 helps mediate NK cell responses against tumor cells. Tumor cells often downregulate HLA class I molecules to evade T-cell recognition, potentially exposing them to NK cell attack. KIR2DL1 recognition of HLA-C downregulation on such cells can modify NK cell responses.
• The inhibitory signal provided by KIR2DL1 upon binding to HLA-C is crucial in preventing inappropriate immune responses. In some cancers, abnormal HLA-C expression can impact KIR2DL1-mediated NK cell inhibition, affecting tumor immunity.

Infectious Diseases:

• During viral infections, some viruses downregulate HLA molecules to escape immune detection by T cells, potentially making infected cells targets for NK cells. KIR2DL1 plays a regulatory role in balancing NK cell responses to infected cells based on HLA expression, which can influence viral clearance.
• The diversity of KIR2DL1 and HLA alleles can influence susceptibility and immune response to certain viruses, including HIV and cytomegalovirus (CMV).

Reproductive Immunology:

• KIR2DL1 has been implicated in reproductive processes, specifically in pregnancy. Interactions between maternal KIR2DL1 on uterine NK cells and fetal HLA-C expressed by trophoblast cells contribute to placental development and immune tolerance during pregnancy.

Clinical Issues

Autoimmune Diseases:

• Variations in KIR2DL1 and its interaction with HLA-C alleles have been linked to autoimmune conditions such as rheumatoid arthritis, psoriasis, and Crohn’s disease. These diseases are associated with altered NK cell function, possibly due to altered KIR-HLA interactions that impact immune regulation.
• Studies suggest that certain KIR2DL1 and HLA-C polymorphisms may predispose individuals to autoimmune diseases by affecting NK cell tolerance and function.

Cancer:

• In cancer, KIR2DL1-HLA-C interactions can modulate NK cell responses to tumor cells. Some tumors exploit this pathway to evade immune detection by upregulating HLA-C, which engages KIR2DL1 and inhibits NK cell-mediated cytotoxicity.
• Therapeutic approaches targeting KIR-HLA interactions are under investigation, aiming to block inhibitory signals in NK cells and enhance their antitumor activity.

Transplantation:

• KIR-HLA compatibility is considered in bone marrow transplantation, where NK cell function can affect transplant outcomes. Certain KIR-HLA mismatches may enhance NK cell activity against leukemia cells, improving transplant success.
• Conversely, mismatches that promote strong inhibitory signaling may reduce graft-versus-leukemia effects, influencing transplant protocols.

Pregnancy Complications:

• Abnormal KIR2DL1-HLA-C interactions are implicated in pregnancy-related complications like preeclampsia. These interactions can influence uterine NK cell behavior, potentially affecting placental development and maternal immune responses.

Summary

KIR2DL1 is an inhibitory receptor on NK cells that binds to HLA-C molecules, playing a critical role in immune surveillance, self-tolerance, and immune responses to infected or transformed cells. Structurally, KIR2DL1 consists of extracellular immunoglobulin-like domains for HLA binding, a transmembrane domain, and a cytoplasmic tail with ITIMs that mediate inhibitory signaling. This receptor modulates NK cell activity in various contexts, including cancer, viral infections, autoimmune diseases, and pregnancy. Variations in KIR2DL1 and its interactions with HLA-C are clinically significant, influencing disease susceptibility, transplant outcomes, and pregnancy complications. Understanding the functions and clinical implications of KIR2DL1 is essential for developing targeted therapies and improving immunological interventions in disease and transplantation settings.