KLRB1

Official Full Name

killer cell lectin like receptor B1

Organism

Homo sapiens

GeneID

3820

Background

Natural killer (NK) cells are lymphocytes that mediate cytotoxicity and secrete cytokines after immune stimulation. Several genes of the C-type lectin superfamily, including the rodent NKRP1 family of glycoproteins, are expressed by NK cells and may be involved in the regulation of NK cell function. The KLRB1 protein contains an extracellular domain with several motifs characteristic of C-type lectins, a transmembrane domain, and a cytoplasmic domain. The KLRB1 protein is classified as a type II membrane protein because it has an external C terminus. [provided by RefSeq, Jul 2008]

Synonyms

NKR; CD161; CLEC5B; NKR-P1; NKRP1A; NKR-P1A; hNKR-P1A;

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Detailed Information

The KLRB1 gene, encoding the protein more commonly known as CD161, is located on human chromosome 12p13.31. KLRB1 belongs to the C-type lectin-like receptor superfamily, and the CD161 protein it encodes is a type II transmembrane protein, meaning its N-terminus is intracellular while its C-terminal functional domains are extracellular. The extracellular segment of CD161 contains a C-type lectin-like domain, enabling recognition and binding of specific carbohydrate ligands, such as the Gal-alpha(1,3)Gal epitope and N-acetylglucosamine.

CD161 is expressed on natural killer (NK) cells, NKT cells, and a broad subset of T lymphocytes, including both CD4+ and CD8+ T cells, particularly Th17 cells and tissue-resident memory T cells. This unique expression pattern makes CD161 a useful marker for identifying and isolating specific functional immune cell subsets and highlights its central role in regulating diverse lymphocyte functions.

Biological Significance

The biological function of CD161 is highly complex and context-dependent, with a core role as an inhibitory receptor, especially in regulating NK cell cytotoxicity. Upon ligand binding, CD161 transmits inhibitory signals intracellularly, restraining NK cell killing activity and interferon-γ production. One identified ligand is CLEC2D, also a C-type lectin-like receptor expressed on various target cells. During NK cell recognition of "non-self" or stressed cells via activating receptors, the CD161–CLEC2D interaction provides a critical inhibitory checkpoint, preventing inadvertent damage to normal self-cells expressing CLEC2D and maintaining self-tolerance.

Figure 1. CD161expressionprofile. (Braud VM, et al., 2022)

CD161's functions extend beyond NK cells. In T cells, particularly CD4+ T cells, CD161 serves as a key marker for IL-17-producing Th17 cells. While its direct signaling role in Th17 differentiation and function is not fully defined, CD161 is thought to stabilize Th17 cell phenotype and function. CD161+ T cells, especially tissue-resident memory subsets, demonstrate enhanced self-renewal capacity and polyfunctional cytokine production, playing specialized roles in mucosal immunity and antitumor responses. Activation of CD161 has been reported to stimulate acid sphingomyelinase, increase intracellular ceramide levels, and activate AKT and RSK1 kinase pathways, collectively regulating T-cell proliferation and survival. Therefore, CD161 functions as a multifunctional immune regulatory hub, maintaining immune homeostasis through inhibitory signaling in NK cells while shaping effector T-cell subsets and functions, with effects highly dependent on cell type, receptor co-expression, microenvironmental cues, and ligand properties.

Clinical Relevance

Clinically, KLRB1/CD161 is significant as both a disease biomarker and a potential immunotherapy target. In infectious and autoimmune diseases, CD161+ T cells-particularly Th17 cells-are closely associated with disease pathogenesis. For instance, abnormal frequencies or functional alterations of CD161+ Th17 cells are often observed in peripheral blood or affected tissues of patients with multiple sclerosis, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Monitoring these cells can help evaluate disease activity and treatment response.

In cancer immunology, CD161 exhibits dual significance. On one hand, high CD161 expression in tumor-infiltrating lymphocytes correlates with better prognosis in multiple solid tumors and hematologic malignancies, possibly reflecting a subset of T cells with robust proliferative and effector potential. On the other hand, as an inhibitory receptor on NK cells and some T-cell subsets, interactions with ligands expressed on tumor cells may directly suppress antitumor immunity, facilitating immune evasion. This makes CD161 an attractive immunotherapy target.

Blocking the CD161–CLEC2D inhibitory axis is under active investigation. Monoclonal antibodies targeting CD161 or CLEC2D could release NK and T cells from inhibition, enhancing recognition and killing of tumor cells-a strategy conceptually similar to successful PD-1/PD-L1 checkpoint inhibitors. Preclinical studies demonstrate that blocking CD161 signaling enhances immune cell cytotoxicity against diverse cancer cells, supporting the rationale for clinical translation. Additionally, in CAR-T cell therapy, knockout of CD161 via gene-editing techniques is being explored as a method to enhance CAR-T cell persistence and efficacy, particularly against tumors expressing CLEC2D.

Beyond oncology, activating CD161 signaling might theoretically suppress pathological Th17 responses or NK cell activity in autoimmune diseases, although this remains at an early stage of investigation. Overall, deepening our understanding of KLRB1/CD161 biology is gradually transforming it from an important cell-surface marker into a promising therapeutic target, with its dual roles across immune contexts offering both opportunities and challenges for precision immunotherapy.

References

Aldemir H, Prod'homme V, Dumaurier MJ, et al. Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol. 2005;175(12):7791-7795.
Braud VM, Meghraoui-Kheddar A, Elaldi R, Petti L, Germain C, Anjuère F. LLT1-CD161 Interaction in Cancer: Promises and Challenges. Front Immunol. 2022 Feb 4;13:847576.
Wyrożemski Ł, Qiao SW. Immunobiology and conflicting roles of the human CD161 receptor in T cells. Scand J Immunol. 2021 Sep;94(3):e13090.

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