David H. Raulet Werner Held Isabel Correa Jeffrey R. Dorfman Ming-Fan Wu Laura Corral Specificity, tolerance and developmental regulation of natural killer cells defined by expression of class I-specific Ly49 receptors Authors' addresses David H. Rauiet, VVoTitr Held, isaM Conta. Jeffrey Dorfman, Ming-Fan Wu. Laura Corral Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California. Berkeley, California. USA Correspondence to: David H. Raulet. Deparlnient of Molecular and Cell Biology and Cancer Research Laboratory, 48 S LSA, University of California, Berkeley, Berkeley, CA 94720-3200. USA. Fax: 510 642-1443. email: raulet@ucliiik4.berkeley.edu Acknowledgements This work was supporled by Grants AI3 5021 and AI39642 from the National Institutes of Health. Summary: Natural killer cells in the mouse express class 1 MHC-spedflc inhibitory receptors of the Ly49 protein family. The receptors mediate inhibition of the lysis of tumor cells and normal cells, and mediate the specificity of bone-marrow graft rejection by NK ceUs in vivo. The function of tliese receptors may be to confer upon NK cells the capacity to distin- guish normal self cells from cells that have down-regulated expression of some or all self-class I molecules, Ly49 receptors discriminate between dif- ferent class I molecules, and are distributed in expression to overlapping subsets of NK ceUs. The receptors appear to interact with class I-MHC res- idues and as.sociated N-glycans, with little or no discrimination of the class I-bound peptide. The Ly49 receptor repertoire may be initially gen- erated by a stochastic process that distributes receptors randomly to differ- ent cells and treats the two alleles of a given Ly49 gene independently. However, class I-MHC-dependent "education" processes shape the func- tional repertoire. The education processes silence potentially auto-aggres- sive NK cells, probably by ensuring that each NK cell expres.ses at least one self-specific Ly49 receptor. In addition, NK cell clones that express multi- ple self-specific Ly49 receptors are disfavored by the education processes, perhaps to confer greater discrimination on to individual NK cells. ews 1997 Vol. 155:41-52 Printed in Denmark Ali rights reserved Copyright € Munksgaard 1997 Immunological Reviews ISSNOlOS-2896 Introduction It is now well established that natural killer (NK) cells express receptors specific for class I major histocompatibility complex (MHC) molecules. The interaction of these receptors wilh class I molecules on target cells leads to a dominant signal that inhibits NK cell effector functions. As will be reviewed in more detail below, the class I-specific receptors come in families of related receptors that discriminate between difTerent class I molecules. The available data indicate that each receptor is expressed by a distinct but overlapping subset of NK cells. Thus, co-expression of two or more different receptors is allowed. In vivo, NK cell populations can attack allogeneic or class 1-defi- cient celis, but generally not self-cells. While direct evidence is sparse, it can be proposed that this class I-specific receptor sys- tem functions to destroy self cells in which expression of one or more self-class I molecules has been extinguished as a con- sequence of infection, transformation or mutation (I). 41