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NK Cell Responsiveness Is Tuned Commensurate with the Number of Inhibitory Receptors for Self-MHC Class I: The Rheostat Model ¹

Nathalie T. Joncker^*, Nadine C. Fernandez^2,*, Emmanuel Treiner^3,*, Eric Vivier and David H. Raulet^4,*

^* Department of Molecular and Cell Biology, University of California, Berkeley, CA 94704; and Centre d’Immunologie de Marseille, Marseille, Cedex, France

Inhibitory receptors that engage self-MHC class I molecules enable NK cells to detect disease-associated loss of MHC class I on surrounding cells. Previous studies showed that some NK cells lack all receptors for self-MHC class I, yet fail to exhibit autoimmunity because they are generally hyporesponsive to stimulation. We asked whether NK cells exist in only two states, responsive and hyporesponsive, corresponding to cells that express or fail to express inhibitory receptors for self-MHC class I. The alternative model is that NK cells vary continuously in their responsiveness, based on variations in the number of different inhibitory and stimulatory receptors they express, which is known to vary. In this study, we show in the murine system that NK cell responsiveness increases quantitatively with each added self-MHC-specific inhibitory receptor. Genetic analysis demonstrated that interactions of each of the receptors with self-MHC class I were necessary to observe augmented responsiveness. These findings suggest that NK cell responsiveness is comparable to a rheostat: it is tuned to an optimal set point depending on the inhibitory and stimulatory interactions encountered in the normal environment, so as to ensure self-tolerance and yet optimize sensitivity to changes in normal cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01AI35021 (to D.H.R.).

² Current address: Centocor, Boulogne-Billancourt, 92100 France.

³ Current address: Institut National de la Santé et de la Recherche Médicale Unité 925, Faculte de Medecine Amiens, 80036 France.

⁴ Address correspondence and reprint requests to Dr. David H. Raulet, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94704. E-mail: raulet{at}berkeley.edu

⁵ Abbreviations used in this paper: β₂m, β₂-microglobulin; MFI, mean fluorescent intensity.

⁶ The online version of this article has supplemental material.

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