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Human natural killer cell receptors and signal transduction
1Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Abstract:
Natural killer (NK) cells express numerous receptors, which continually engage with ligands on cell surfaces. Until 1995, only a handful of these receptors were characterized and the molecular basis of NK cell activation was obscure. Recently, considerable advances have been made in characterizing the receptor repertoire on human NK cells. Both activating and inhibitory receptors can transduce positive or negative signals to regulate NK cell cytotoxicity and cytokine release responses. The inhibitory receptors normally predominate in this balance of signals. Certain tumor cells and virally infected cells that lack major histocompatibility complex (MHC) class I molecules, however, can rapidly trigger NK cell activation. The basis of this activation is the loss of negative signals that are normally transmitted by MHC class I-binding inhibitory receptors, and the corresponding domination of activating receptor signals. While ligand specificity for a number of the recently described receptors is still a mystery, their signal transduction properties have begun to be defined. The dynamic crosstalk between these receptors ultimately governs the NK cell activation state. Although the complexities of NK cell signalling are only marginally understood, several overall themes have been defined by characterizing the roles of distinct pathways during NK cell responses.
Insights
Natural killer (NK) cells use activating and inhibitory receptors to control cell killing. Loss of MHC class I on tumor cells triggers NK cell activation by removing inhibitory signals.
Area of Science:
- Immunology
- Cell Biology
Background:
- Natural killer (NK) cells are crucial for innate immunity, mediating cytotoxicity and cytokine release.
- NK cell function is regulated by a complex interplay of activating and inhibitory receptors engaging cell surface ligands.
- Prior to 1995, the molecular mechanisms governing NK cell activation were largely unknown.
Purpose of the Study:
- To elucidate the molecular basis of NK cell activation and the roles of various receptors.
- To understand how the balance of signals from activating and inhibitory receptors regulates NK cell responses.
- To define the signal transduction properties of recently characterized NK cell receptors.
Main Methods:
- Characterization of the human NK cell receptor repertoire.
- Analysis of signal transduction pathways initiated by NK cell receptors.
- Investigation of NK cell responses to target cells with varying MHC class I expression.
Main Results:
- Both activating and inhibitory receptors modulate NK cell cytotoxicity and cytokine release.
- Inhibitory receptors, typically dominant, bind to Major Histocompatibility Complex (MHC) class I molecules.
- Loss of MHC class I on target cells disengages inhibitory receptors, leading to NK cell activation via dominant activating signals.
Conclusions:
- NK cell activation is governed by the dynamic balance between signals from activating and inhibitory receptors.
- The absence of MHC class I on target cells is a key trigger for NK cell-mediated killing.
- While ligand specificities are still being uncovered, the signal transduction roles of NK cell receptors are becoming clearer, revealing themes in NK cell pathway regulation.