A common polymorphism in the human immunoreceptor NKp65 determines ligand interaction, cell surface expression and
Julian Leonard Lino Heller1, Yvonne Bartel1, Catalin Schach1
1Institute for Molecular Medicine, Goethe-University Frankfurt, Frankfurt am Main, Germany.
Plos One
|August 13, 2025
Summary
A common genetic variation in the KLRF2 gene (rs576601) impacts NKp65 function. This polymorphism reduces NKp65 surface expression and ligand binding, impairing cellular cytotoxicity and potentially skin immunosurveillance.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- NKp65 is an immunoreceptor expressed on innate lymphoid cells group 3 (ILC3).
- NKp65 interacts with its ligand KACL to activate cellular cytotoxicity.
- A common polymorphism in the KLRF2 gene (rs576601) was investigated for its functional relevance.
Purpose of the Study:
- To investigate the impact of the KLRF2 gene polymorphism rs576601 on NKp65.
- To analyze how this polymorphism affects NKp65 surface expression, ligand binding, and cellular function.
Main Methods:
- Biophysical methods including flow cytometry and surface resonance spectroscopy.
- Immunological methods such as ELISA and immunoblots.
- Cytotoxicity assays were employed to assess functional responsiveness.
Main Results:
- The rs576601 polymorphism results in an amino acid substitution (Pro131Thr) in NKp65.
- The NKp65-Thr131 variant exhibits reduced cell surface expression due to enhanced intracellular retention.
- This polymorphism significantly alters KACL binding kinetics and affinity, leading to reduced cellular cytotoxicity.
Conclusions:
- The rs576601 polymorphism impairs NKp65 function by affecting ligand interaction and surface expression.
- Given KACL's expression on keratinocytes, this polymorphism may influence skin immunosurveillance by NKp65-expressing ILC3.
Related Concept Videos
01:28Diversity of Antigen Receptors
799
Antigen receptors are essential components of the immune system crucial in defending the body against foreign invaders. These receptors are present on the surface of B and T cells, enabling them to recognize antigens and mount an appropriate immune response.
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
799
01:28Cells of the Innate Immune Response
3.2K
The innate immune response is an immediate and non-specific response against pathogens, acting swiftly to prevent the spread of infections. The primary cells involved in this response are phagocytes and natural killer (NK) cells.
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
3.2K
02:26NF-κB-dependent Signaling Pathway
7.8K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
7.8K
01:15Receptor Downregulation in MVBs
2.1K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.1K
01:22T Cell Activation and Clonal Selection
4.6K
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...
4.6K
01:25Immune Surveillance by NK Cells and Phagocytes
2.8K
Immune surveillance is an integral part of the innate immune system, involving the continuous monitoring of peripheral tissues to detect and respond to pathogens, infected cells, or cancerous cells. This surveillance is conducted primarily by natural killer (NK) cells and phagocytes, which employ distinct but complementary mechanisms to identify and eliminate threats.
Natural Killer Cells: The Fast Responders
NK cells are large granular lymphocytes found in the blood and lymphatic system. These...
Natural Killer Cells: The Fast Responders
NK cells are large granular lymphocytes found in the blood and lymphatic system. These...
2.8K