Abstract
In this study we have addressed the question of how activation and inhibition of human NK cells is regulated by the expression level of MHC class I protein on target cells. Using target cell transfectants sorted to stably express different levels of the MHC class I protein HLA-Cw6, we show that induction of degranulation and that of IFN-γ secretion are not correlated. In contrast, the inhibition of these two processes by MHC class-I occurs at the same level of class I MHC protein. Primary human NK cell clones were found to differ in the amount of target MHC class I protein required for their inhibition, rather than in their maximum killing capacity. Importantly, we show that KIR2DL1 expression determines the thresholds (in terms of MHC I protein levels) required for NK cell inhibition, while the expression of other receptors such as LIR1 is less important. Furthermore, using mathematical models to explore the dynamics of target cell killing, we found that the observed delay in target cell killing is exhibited by a model in which NK cells require some activation or priming, such that each cell can lyse a target cell only after being activated by a first encounter with the same or a different target cell, but not by models which lack this feature.
Highlights
Natural Killer (NK) cells are lymphocytes capable of cytotoxicity and cytokine secretion, which interact with other cells and have an important role in certain anti-viral and anti-tumor immune responses
We have previously shown that there is a clear threshold in the amount of target cell surface Human Leukocyte Antigen (HLA)-C protein required for inhibition of NK cell cytotoxicity [1]
NK cell clones differ from each other mostly in their activation/inhibition thresholds In order to understand how KIR2DL1 expression levels determine NK cell activation/inhibition thresholds, we mathematically modelled the dependence of the killing rate k on the product of the numbers of Killer cell Immunoglobulin-like Receptor (KIR) and MHC molecules by a sigmoid threshold function, where S denotes the threshold of the NK cell clone in the same experiment, in units of2 as it is given in terms of the MHC and KIR numbers (MHC*KIR) product
Summary
Natural Killer (NK) cells are lymphocytes capable of cytotoxicity and cytokine secretion, which interact with other cells and have an important role in certain anti-viral and anti-tumor immune responses. Their response is determined by the integration of activating and inhibitory signals and one important unknown is how these signals are integrated. We have previously shown that there is a clear threshold in the amount of target cell surface Human Leukocyte Antigen (HLA)-C protein required for inhibition of NK cell cytotoxicity [1]. Expression of the activating ligand MICA changes the thresholds for inhibition of NK cell cytotoxicity mediated by the target cell MHC-I levels [3]. It is important to elucidate the effects of MHC expression levels on NK cell inhibition
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