1. Howard Hughes Medical Institute, Rheumatology Division, Departments of Medicine,
2. Pathology and Immunology,
3. Pediatrics and
4. Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
5. Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V 1B7, Canada
6. †Present address: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tuscon, Arizona 85724, USA

Correspondence to: Wayne M. Yokoyama^1,2 Correspondence and requests for materials should be addressed to W.M.Y. (Email: yokoyama@wustl.edu).

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 cells^{2, 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 genes^{5, 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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