Licensing of natural killer cells by host major histocompatibility complex class I molecules

Sungjin Kim, Jennifer Poursine-Laurent, Steven M. Truscott, Lonnie Lybarger, Yun-Jeong Song, Liping Yang, Anthony R. French, John B. Sunwoo, Suzanne Lemieux, Ted H. Hansen and Wayne M. Yokoyama ()
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Sungjin Kim: Howard Hughes Medical Institute
Jennifer Poursine-Laurent: Howard Hughes Medical Institute
Steven M. Truscott: Pathology and Immunology
Lonnie Lybarger: Pathology and Immunology
Yun-Jeong Song: Howard Hughes Medical Institute
Liping Yang: Howard Hughes Medical Institute
Anthony R. French: Howard Hughes Medical Institute
John B. Sunwoo: Howard Hughes Medical Institute
Suzanne Lemieux: Université du Québec
Ted H. Hansen: Pathology and Immunology
Wayne M. Yokoyama: Howard Hughes Medical Institute

Nature, 2005, vol. 436, issue 7051, 709-713

Abstract: Abstract 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.

Date: 2005
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DOI: 10.1038/nature03847

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