KLRD1 - killer cell lectin like receptor D1 |Elisa - Clia - Antibody - Protein

Background

Killer Cell Lectin-Like Receptor D1 (KLRD1), commonly known as CD94, is a transmembrane protein that plays a crucial role in the immune system. Expressed on the surface of natural killer (NK) cells and certain subsets of T-cells, KLRD1 is primarily involved in recognizing and responding to infected or transformed cells. KLRD1 is part of the C-type lectin-like family of receptors, and its main function is to pair with other receptors (e.g., NKG2 family members) to mediate immune surveillance by recognizing peptide-loaded MHC class I molecules. Unlike other immune receptors that directly recognize pathogenic antigens, KLRD1 primarily regulates immune response through interaction with HLA-E, a non-classical MHC class I molecule presenting peptide sequences derived from other MHC class I molecules.

The KLRD1 gene is located on chromosome 12 in humans, within the NK gene complex region, alongside genes encoding various other NK cell receptors. This locus is highly conserved across species, underscoring the essential function of KLRD1 in immune defense and pathogen recognition. The KLRD1 protein forms heterodimers with different NKG2 family members, creating receptors that can either activate or inhibit NK cell responses depending on the specific NKG2 pairing. These heterodimers enable the immune system to maintain a balanced response, effectively recognizing and eliminating infected or malignant cells while avoiding the destruction of healthy cells. Due to its regulatory role in immune responses, KLRD1 is a target of interest in therapies related to cancer, infectious diseases, and immune-modulating treatments.

Protein Structure

KLRD1 is a single-pass type II transmembrane protein approximately 179 amino acids in length. Its structure contains several domains that facilitate ligand binding and signaling in NK and T cells, which include:

Extracellular C-type Lectin-like Domain (CTLD):

• The most critical structural component of KLRD1 is its C-type lectin-like domain (CTLD), located on the extracellular portion of the protein. This domain is not a classic C-type lectin domain, as it lacks the calcium-binding sites typical of these proteins, but it has a similar folding structure that allows for ligand interactions.
• The CTLD in KLRD1 mediates binding to HLA-E molecules loaded with peptides, which provides a recognition mechanism for cells presenting MHC class I-derived peptides. This domain is vital for immune response regulation, as binding to HLA-E can either inhibit or activate NK cell activity based on the peptide presented and the receptor it partners with on NK cells.

Transmembrane Domain:

• KLRD1 contains a single transmembrane domain that anchors the protein within the plasma membrane of NK and T cells. This domain is essential for stabilizing KLRD1 and for forming heterodimers with NKG2 receptors, enabling functional signaling complexes on the cell surface.
• This domain is hydrophobic, facilitating integration within the lipid bilayer of the cell membrane and assisting with stable receptor-ligand interaction during immune surveillance.

Cytoplasmic Tail:

• KLRD1 has a relatively short cytoplasmic tail, which does not contain any known signaling motifs. This lack of intrinsic signaling capability means that KLRD1 relies on its interaction with NKG2 receptors, which have intracellular signaling capabilities, to mediate downstream effects in NK and T cells.

Classification and Subtypes

KLRD1 is part of the killer cell lectin-like receptor (KLR) family, specifically classified under the C-type lectin domain (CTLD) family of immune receptors. KLRD1 does not have subtypes but can form heterodimers with several different NKG2 family members (such as NKG2A, NKG2C, and NKG2E). These heterodimers give rise to functionally distinct receptor complexes with different biological activities:

Inhibitory Receptor Complex (CD94/NKG2A):

• The CD94/NKG2A complex is an inhibitory receptor that binds to HLA-E and transmits inhibitory signals to NK cells, preventing the immune response against healthy cells displaying appropriate HLA-E signals.

Activating Receptor Complex (CD94/NKG2C and CD94/NKG2E):

• The CD94/NKG2C and CD94/NKG2E complexes act as activating receptors when they bind to HLA-E molecules presenting stress-related or pathogen-derived peptides. This signaling activates NK cells, promoting cytokine release and cytotoxic activity against abnormal or infected cells.

Function and Biological Significance

KLRD1, through its heterodimerization with NKG2 receptors, plays a critical role in:

Immune Surveillance:

• KLRD1 enables NK cells to detect changes in MHC class I molecule presentation. This function is essential for identifying cells under stress, such as during viral infections or tumorigenesis, as these cells often show altered or reduced MHC class I expression.

Regulation of NK Cell Activation:

• By pairing with NKG2A (inhibitory) or NKG2C/E (activating) receptors, KLRD1 is instrumental in balancing NK cell activity, ensuring immune tolerance to healthy cells while enabling targeted elimination of infected or malignant cells.

Adaptive Immunity and Immune Memory:

• KLRD1 has been implicated in adaptive-like immune responses, particularly in situations where NK cells exhibit memory-like responses, such as during certain viral infections (e.g., cytomegalovirus). CD94/NKG2C receptors allow NK cells to adapt and recall responses to previous infections, resembling adaptive immunity traditionally associated with T and B cells.

Modulation of T Cell Responses:

• KLRD1 is also expressed on subsets of CD8+ T cells, where it may play a role in modulating cytotoxic T cell responses. This function is crucial for maintaining a controlled immune response during chronic infections or in response to tumors, where an overactive T cell response could lead to tissue damage.

Role in Inflammation and Infection:

• During viral infections, such as by CMV or HIV, KLRD1 expression levels may shift to allow NK cells to become more responsive to infected cells. This upregulation or modulation of KLRD1 contributes to antiviral immunity, helping clear infected cells while preserving uninfected tissue.

Clinical Issues

Cancer:

• Alterations in KLRD1 expression or function have been associated with various cancers. Tumor cells often evade immune detection by modifying HLA-E expression, disrupting KLRD1-mediated NK cell responses.
• Therapeutic strategies targeting KLRD1-NKG2 interactions are being explored to enhance NK cell activity against cancer cells, offering a potential avenue for immunotherapy in oncology.

Infectious Diseases:

• KLRD1 is involved in immune responses to several infectious diseases. Cytomegalovirus (CMV) infection, for example, has been shown to influence KLRD1-NKG2 receptor expression, resulting in a memory-like response that enhances the immune system’s ability to respond to subsequent infections.
• Modulation of KLRD1 interactions may also play a role in controlling HIV infection, where immune evasion by the virus affects NK cell function.

Autoimmune Diseases:

• Dysregulation of KLRD1 and its associated receptor complexes can contribute to autoimmune diseases. In conditions like rheumatoid arthritis and systemic lupus erythematosus, altered KLRD1 signaling may contribute to excessive NK cell activation, leading to tissue damage.

Transplantation:

• KLRD1 expression levels can influence outcomes in organ and bone marrow transplants. As KLRD1 helps regulate NK cell activity, it has been investigated as a potential biomarker for predicting transplant rejection or acceptance. Strategies to modulate KLRD1 function could improve transplant success by reducing immune-mediated tissue rejection.

Summary

KLRD1 (CD94) is a critical receptor on NK and certain T cells, involved in regulating immune responses through interactions with HLA-E and NKG2 receptors. Its structure includes a C-type lectin-like domain for ligand binding, a transmembrane region for membrane stability, and a short cytoplasmic tail. Functionally, KLRD1 plays an essential role in balancing immune activation and inhibition, allowing NK cells to recognize and eliminate infected or transformed cells without targeting healthy tissue. Clinically, KLRD1’s interactions influence disease outcomes in cancer, infections, autoimmune disorders, and transplant tolerance. Its complex role in immune surveillance makes it a promising target for therapeutic interventions in immune-mediated diseases and cancer.