Human NK Cells Differ More in Their KIR2DL1-Dependent Thresholds for HLA-Cw6-Mediated Inhibition than in Their Maximal Killing Capacity

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.

Models and methods for analysis of lymphocyte repertoire generation, development, selection and evolution

“…Second, findings by several groups reveal long-lived memory NK cells generated after viral responses, which are better at responding to secondary challenges [15,16]. Our own studies [17], exploring the kinetics of target cell killing by NK cells using mathematical models, also support the notion that resting NK cells become more likely to kill target cells after the first target cell encounter. Since NK cell receptors are one of the fastest evolving molecular systems [18], NK cells can no longer be regarded as an evolutionary relic from a more primitive immune system; rather, they are a functional and evolutionary bridge between innate and adaptive immunity [19].…”

Maternal uterine NK cell–activating receptor KIR2DS1 enhances placentation

“…This contrasts with pbNK, where tuning down of KIR2DS1 responses to HLA-C2 was observed only in HLA-C2 homozygotes (25,26,29,30). The rheostat model of NK education proposes that NK cell function is "tuned" by interactions between inhibitory and activating receptors on the cell and their ligands during NK development, and quantity of MHC also affects NK cell responsiveness (48,49). Indeed, we show that dNK appear to be more sensitive to lower levels of HLA-C, and this may explain why we found evidence of dNK tuning via KIR2DS1 even in C2/C1 heterozygotes.…”

Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

“…Similar to the situation with CTL, it is likely that the relatively small inhibition in cell surface MHC class I expression is insufficient to alter NK cell recognition. The existence of a threshold of NK cell activation/inhibition regulated by MHC class I levels [26,45,46] In colorectal cancer, patients whose tumours expressed high levels of MHC class I showed similar survival times to those whose tumours had lost MHC class I [47]. However, patients with reduced MHC class I expression had the worst prognosis of these three groups; the authors of this study suggest that reduced MHC class I levels on these tumours might be insufficient to mediate CTL recognition but are nevertheless still capable of inhibiting NK cell activity, rendering the tumour resistant to both classes of cytotoxic lymphocytes [47].…”