KLRB1 - killer cell lectin like receptor B1 |Elisa - Clia - Antibody - Protein

Background

Killer cell lectin-like receptor B1 (KLRB1), also known as CD161, is a type II transmembrane protein predominantly expressed on subsets of immune cells, especially natural killer (NK) cells and T cells. KLRB1 plays a key role in modulating immune responses and is especially involved in the regulation of cytotoxicity and cytokine production, particularly among NK and T cell subsets. KLRB1 belongs to the C-type lectin superfamily and is encoded by the KLRB1 gene located on chromosome 12p13 in humans. KLRB1’s expression is associated with an inhibitory effect on immune cell activation, helping maintain immune homeostasis, prevent excessive immune responses, and aid in the modulation of immune activity against infections, tumors, and in inflammatory diseases.

KLRB1 is primarily known for its role as a receptor for the carbohydrate-bearing protein LLT1 (lectin-like transcript 1, or CLEC2D). This interaction facilitates cell-cell communication and can mediate inhibitory signaling in NK cells and some T cell subsets, potentially leading to immune tolerance in certain tissues and tumors.

Protein Structure

KLRB1 has a distinct structural design typical of the C-type lectin family, with specific domains that facilitate its function in immune regulation:

Extracellular Domain (C-type Lectin Domain):

• The extracellular domain contains the C-type lectin-like domain (CTLD), a hallmark structure that allows for binding to carbohydrate ligands. Despite being part of the C-type lectin family, KLRB1’s ligand-binding mechanism does not depend on calcium, unlike most C-type lectins.
• The CTLD in KLRB1 is a beta-sheet-rich structure forming a stable, elongated domain, which facilitates binding to LLT1 on target cells. This binding interface is essential for KLRB1-mediated signaling, as it enables the receptor-ligand interactions necessary for modulating immune cell responses.

Transmembrane Domain:

• KLRB1 is anchored to the cell membrane through a hydrophobic transmembrane domain, stabilizing its presence on the surface of NK and T cells. This domain spans the plasma membrane and assists in positioning the receptor to effectively engage with ligands in the extracellular environment.

Cytoplasmic Tail:

• The cytoplasmic tail of KLRB1 does not contain classical signaling motifs, such as immunoreceptor tyrosine-based activation motifs (ITAMs) or immunoreceptor tyrosine-based inhibition motifs (ITIMs). Instead, KLRB1 signaling is indirectly mediated through adaptor proteins that interact with the cytoplasmic region. This structure suggests that KLRB1’s signaling role relies heavily on secondary signaling pathways rather than direct intracellular modulation.

Classification and Subtypes

KLRB1 is part of the C-type lectin family and is specifically classified under the NK cell receptor group, which comprises several receptors with immune-regulatory functions. While KLRB1 itself does not have distinct isoforms or subtypes, it shares structural similarities with other members of the C-type lectin family, such as NKG2A, NKG2C, and NKG2D. These receptors often work together in NK and T cells, coordinating immune responses by binding to various ligands on target cells.

Function and Biological Significance

KLRB1’s primary biological functions center on immune modulation, particularly influencing NK cell and T cell activities:

Regulation of NK Cell Cytotoxicity:

• KLRB1 serves as an inhibitory receptor on NK cells. When engaged by LLT1 on a target cell, KLRB1 transmits inhibitory signals that reduce the cytotoxic response, essentially preventing NK cells from killing the target cell. This regulatory function is crucial in protecting healthy cells from immune-mediated damage, particularly in tissues where NK cells might otherwise respond inappropriately.
• The interaction with LLT1 allows KLRB1 to play a role in immune surveillance by controlling NK cell activity, maintaining immune homeostasis, and contributing to self-tolerance.

Modulation of T Cell Activity:

• KLRB1 is also expressed on a subset of T cells, particularly on CD4+ T helper 17 (Th17) cells and CD8+ T cells. Its presence on T cells suggests a role in moderating immune responses, particularly in inflammatory conditions.
• In Th17 cells, KLRB1 may help balance pro-inflammatory responses by limiting excessive activation, reducing cytokine production, and preventing tissue damage from inflammation.

Immune Tolerance and Tissue-Specific Immunity:

• KLRB1 plays a role in tissue-specific immune tolerance, particularly within the liver and gastrointestinal tract, where immune cells must carefully regulate their activity to avoid damaging essential tissues.
• By providing inhibitory signals, KLRB1 aids in immune tolerance against tissue-resident cells, preventing inappropriate immune responses in specific microenvironments, such as those found in mucosal tissues.

Tumor Immunology:

• In the tumor microenvironment, LLT1 expression on tumor cells can interact with KLRB1 on NK cells, reducing their ability to kill tumor cells. This mechanism allows some tumors to evade immune detection, highlighting KLRB1’s role in immune surveillance and its potential as a therapeutic target.
• Blocking KLRB1-LLT1 interactions has been proposed as a strategy for reinvigorating NK cell activity against tumors, thereby enhancing anti-tumor immunity.

Clinical Issues

KLRB1’s function as an inhibitory receptor has implications in several clinical settings, particularly in cancer, chronic infections, and autoimmune diseases:

Cancer:

• Elevated LLT1 expression on tumor cells can exploit KLRB1-mediated inhibition, allowing cancer cells to evade NK cell-mediated cytotoxicity. Research into KLRB1-LLT1 blockade as an immunotherapy strategy is ongoing, with the aim of restoring immune surveillance and enhancing NK cell responses against cancerous cells.
• KLRB1 is therefore a potential target in cancer immunotherapy, where blocking its inhibitory effects could improve immune recognition and destruction of tumor cells.

Autoimmune Diseases:

• In autoimmune diseases, dysregulation of KLRB1 signaling may contribute to chronic inflammation and tissue damage, particularly in diseases where NK and T cell activation are misdirected. Enhanced KLRB1 signaling could theoretically help dampen excessive immune responses in autoimmune conditions, although more research is needed.
• KLRB1 expression on Th17 cells, which are involved in inflammatory responses, highlights its potential relevance in autoimmune conditions characterized by Th17 activity, such as rheumatoid arthritis and multiple sclerosis.

Chronic Infections:

• Chronic viral infections, such as HIV and hepatitis, may induce alterations in KLRB1 expression or function. Increased KLRB1 expression in response to persistent antigen exposure can contribute to immune cell exhaustion, reducing the ability of NK and T cells to control infection over time.
• The manipulation of KLRB1 signaling could potentially restore function in exhausted immune cells, improving immune control over chronic infections.

Summary

KLRB1 (CD161) is a type II transmembrane protein within the C-type lectin family, primarily expressed on NK and T cells. Structurally, it features a C-type lectin-like domain that binds to LLT1 on target cells, initiating inhibitory signaling pathways that modulate immune activity. KLRB1 serves critical roles in immune homeostasis, helping to prevent inappropriate immune cell activation and supporting tissue-specific tolerance, particularly in mucosal tissues and tumor microenvironments.

KLRB1’s inhibitory functions are biologically significant in regulating cytotoxic responses, modulating Th17 cell activity, and promoting immune tolerance. Its clinical relevance spans various fields, including cancer, where KLRB1-LLT1 interactions enable tumor immune evasion; chronic infections, where it contributes to immune exhaustion; and autoimmune diseases, where it may mitigate excessive inflammation.