KLRC - killer cell lectin like receptor C |Elisa - Clia - Antibody - Protein

Background

The Killer cell lectin-like receptor C (KLRC) gene family, also known as NKG2, plays an integral role in the immune system by regulating the activity of natural killer (NK) cells and some T-cell subsets. KLRC genes encode receptors involved in recognizing stressed or infected cells, facilitating an appropriate immune response. They are essential in immune surveillance, especially for identifying cells infected by viruses or transformed into tumor cells. Unlike other receptors that rely on immunoglobulin domains, KLRC receptors belong to the C-type lectin-like receptor superfamily, characterized by the presence of a carbohydrate-recognition domain, which structurally resembles that found in lectins. However, KLRC receptors do not typically bind carbohydrates but instead interact with non-classical MHC class I molecules, specifically human leukocyte antigen-E (HLA-E) in humans.

The KLRC family consists of several key genes, including KLRC1 (NKG2A), KLRC2 (NKG2C), KLRC3 (NKG2E), and KLRC4 (NKG2F), which encode proteins with distinct functional profiles. The KLRC genes are located on chromosome 12, often close to other NK cell receptors, and their expression varies across individuals and populations, contributing to genetic diversity in immune response.

Protein Structure

The KLRC protein structure is defined by its extracellular lectin-like domain, which facilitates binding to HLA-E and similar ligands, its transmembrane region, and a short cytoplasmic tail responsible for signaling in some KLRC variants.

Extracellular Lectin-like Domain:

• The extracellular domain of KLRC proteins resembles a C-type lectin fold, characterized by a double-layered beta-sheet structure connected by a loop region. Although this domain does not bind carbohydrates, it allows KLRC proteins to bind specifically to HLA-E.
• The interaction surface within the lectin-like domain of KLRC receptors aligns with the peptide-binding groove of HLA-E. This specificity is integral for recognizing HLA-E and indirectly monitoring the presence of peptides from other MHC molecules or viral antigens presented by HLA-E.

Transmembrane Domain:

• KLRC receptors possess a hydrophobic transmembrane domain that anchors the receptor to the NK or T cell membrane. Notably, KLRC1 (NKG2A) has a unique neutral transmembrane region, allowing for inhibitory signaling, whereas KLRC2 (NKG2C) contains a charged amino acid that associates with adaptor proteins to transmit activating signals.
• The presence of positively charged residues in the transmembrane domain of KLRC2 enables it to associate with the DAP12 adaptor protein, essential for transmitting activating signals within the cell.

Cytoplasmic Tail:

• KLRC1 (NKG2A) has an immunoreceptor tyrosine-based inhibitory motif (ITIM) within its cytoplasmic tail, responsible for recruiting phosphatases upon ligand binding, which dampens cellular activation.
• KLRC2 (NKG2C), KLRC3 (NKG2E), and KLRC4 (NKG2F) lack ITIMs and instead rely on adaptor proteins, such as DAP12, to initiate signaling cascades that lead to NK cell activation and cytokine production.

Classification and Subtypes

The KLRC gene family comprises several subtypes that vary in their signaling capacities and immune functions:

KLRC1 (NKG2A):

• An inhibitory receptor that interacts with HLA-E. The cytoplasmic tail of KLRC1 contains ITIM motifs, which recruit phosphatases like SHP-1 and SHP-2 to counteract activation signals.

KLRC2 (NKG2C):

• An activating receptor, also interacting with HLA-E but associates with the DAP12 adaptor to promote cellular activation.

KLRC3 (NKG2E):

• Similar in structure and function to KLRC2, though less common. KLRC3 is also an activating receptor and binds to HLA-E, promoting NK cell responses.

KLRC4 (NKG2F):

• KLRC4 is another activating receptor, though it is less well understood in terms of ligand specificity and biological function compared to other KLRC receptors.

Function and Biological Significance

KLRC receptors are crucial for immune regulation, particularly in NK cell-mediated surveillance. They modulate the activation status of NK cells based on interactions with HLA-E, an MHC class Ib molecule presenting peptides derived from other MHC molecules or viral proteins.

Immune Surveillance and Tumor Recognition:

• KLRC1 and KLRC2 receptors allow NK cells to detect and respond to changes in HLA-E expression on target cells. When HLA-E expression decreases, typically due to cellular stress, infection, or malignant transformation, the balance of signals shifts towards activation, promoting NK cell cytotoxicity.
• The interaction of KLRC receptors with HLA-E ensures that NK cells can indirectly assess the health of cells by monitoring the integrity of the MHC class I pathway, a mechanism often compromised in infected or transformed cells.

Virus Infection and Adaptive Immunity:

• During viral infections, some viruses manipulate the host's HLA-E expression to evade immune detection. KLRC1 (NKG2A) can serve as an immune checkpoint, dampening NK cell responses in such cases. However, the activating receptor KLRC2 (NKG2C) may bypass this inhibition, enhancing immune responses against cells presenting viral peptides via HLA-E.
• KLRC receptors are also expressed on some CD8+ T cells, providing an additional layer of immune regulation.

Crosstalk Between Activating and Inhibitory Receptors:

• The balance between KLRC1 (inhibitory) and KLRC2/KLRC3 (activating) receptors is essential for preventing unintended immune responses. This balance ensures immune tolerance while enabling rapid activation when pathogen-associated molecular patterns are detected.

Clinical Issues

KLRC receptors are implicated in various disease states due to their central role in immune regulation. Genetic variations within the KLRC gene family can influence susceptibility to infections, autoimmune disorders, cancer, and outcomes in hematopoietic stem cell transplantation.

Cancer:

• In cancers, NK cells play a role in recognizing and eliminating tumor cells that have downregulated MHC class I molecules. The presence of activating KLRC2 (NKG2C) receptors enhances NK cell function against tumors. Studies have shown that high KLRC2 expression can contribute to better control of certain cancers.
• Conversely, the inhibitory KLRC1 (NKG2A) receptor may facilitate immune evasion by tumors. Therapies targeting KLRC1 to block inhibitory signaling and enhance KLRC2-mediated activation are being explored in immunotherapy.

Viral Infections:

• KLRC2 (NKG2C) receptors are particularly relevant in infections with human cytomegalovirus (HCMV), which manipulates HLA-E expression. NKG2C+ NK cells expand in response to HCMV, enhancing the immune system's ability to combat the virus. Individuals with certain KLRC polymorphisms exhibit more robust responses to HCMV and other viral infections.
• These polymorphisms can affect not only susceptibility to viral infections but also disease severity, as variations in receptor expression can influence NK cell activity.

Autoimmune Disorders:

• Dysregulation in KLRC receptor signaling has been associated with autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Inhibitory signals from KLRC1 may contribute to immune tolerance mechanisms, while activating signals from KLRC2 may exacerbate autoimmune responses in genetically predisposed individuals.
• KLRC1-NKG2A blockade is being investigated to reduce inhibitory signaling, potentially balancing immune activation in autoimmune conditions.

Transplantation:

• In hematopoietic stem cell transplantation (HSCT), the compatibility of KLRC genes between donor and recipient influences post-transplant outcomes. Activating KLRC2 expression may promote graft-versus-tumor effects, while inhibitory KLRC1 expression can increase the risk of relapse. Monitoring KLRC gene expression is thus relevant for HSCT prognosis and therapeutic strategies.

Summary

The KLRC gene family, encoding NKG2 receptors, is vital for NK cell-mediated immune surveillance and regulation. The extracellular lectin-like domains of KLRC proteins facilitate binding to HLA-E, an MHC class I molecule that allows NK cells to assess cellular health indirectly. KLRC1 serves as an inhibitory checkpoint receptor, while KLRC2 and KLRC3 act as activating receptors, with KLRC4 playing a less characterized role. The balanced signaling between these receptors is crucial for effective immune responses, particularly in virus infections and cancer. KLRC genetic variations influence susceptibility to infection, cancer, autoimmune disorders, and transplantation outcomes, highlighting their clinical significance. Emerging therapies target KLRC1 to enhance immune responses, offering promising avenues in immunotherapy and treatment of infectious diseases.