Natural killer cell receptors: The offs and ons of NK cell recognition

Abstract

David H. Raulet and Werner Held Department of Molecular and Cell Biology and Cancer Research Laboratory University of California Berkeley, California 94720 Natural killer (NK) cells constitute a distinct lineage of lym- phocytes that kill a variety of target cells, including tumor cells, cells infected with some viruses or bacteria, and some normal cell types. NK cells resemble cytotoxic T lymphocytes (CTLs) in some respects, including cytokine production and the use of the perforin-dependent cytolytic machinery. Significantly, however, NK cells do not ex- press T cell receptors or immunoglobulins, and they are apparently unaffected by defects in the V-D-J recombina- tion machinery. Furthermore, early efforts to define dis- crete patterns of recognition by NK cells met with failure, leading to the notion that NK recognition is primitive. However, recent results suggest that target cell lysis by NK cells is regulated by a balance between specific activating and inhibitory receptors. A major component of recogni- tion involves receptors specific for class I major histocom- patibility complex (MHC) molecules on target cells, en- gagement of which inhibits N K lysis. Thus, cells exhibiting abnormal or reduced amounts of class I molecules, which are therefore invisible to CTLs, are killed by NK cells. The recent characterization of several novel recognition struc- tures on NK cells has added a wealth of new information, but at the same time has generated a number of fascinat- ing puzzles. Recognition of Class I MHC Molecules by NK Cells The role of NK ceils in bone marrow allograft rejection was the initial hint that they recognize MHC molecules (for review see Yu et al., 1992). Then it was discovered that the sensitivity of many tumor cells to lysis by NK cells in vitro is inversely related to the levels of MHC class I molecules on the tumor cells (for review see Ljunggren and Karre, 1990), a finding later extended to nontransformed lymphoblasts from class I-deficient mice (Liao et al., 1991). Class I molecules on target cells somehow prevent NK cell-mediated lysis. The situation proved more complex when it was appreci- ated that NK cells can discriminate class I alleles. Human NK clones were shown to lyse allogeneic T cell blasts, and the target cell genes controlling susceptibility to lysis were mapped to the MHC (Ciccone et al., 1992). In the murine system, an NK cell subset defined by expression of the Ly49A moleculewas shown to discriminate between tumor target cells expressing different MHC haplotypes (Karl- hofer et al., 1992). Class I Expression by Target Cells Inhibits NK Cells and Activates T Cells Fragments of intracellular protein antigens are presented by MHC class I molecules on the cell surface. Hence, class I molecules allow specific recognition and lysis of infected