Self versus non-self discrimination is a central theme in biology from plants1 to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells2,3,4. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes5,6. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through ‘licensing’ by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells—licensed or unlicensed—and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.
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Work in the Yokoyama laboratory is supported by the Howard Hughes Medical Institute, the Barnes-Jewish Hospital Foundation and grants from the National Institutes of Health. Transgenic production and genotyping were supported by the Rheumatic Diseases Core Center grant. This study was also supported by an NIH grant to the Hansen laboratory. The authors thank M. Miley and D. Fremont for initial production of the SCT–Kb tetramers, E. Holroyd, J. Mohan, D. Higuchi and R. Rodrigues for technical assistance, and P. Allen, M. Colonna, J. Loh and E. Unanue for critical comments on the manuscript.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
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Kim, S., Poursine-Laurent, J., Truscott, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005). https://doi.org/10.1038/nature03847
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