Turning on Natural Killer Cells

NK cells preferentially recognize and kill cells that lack expression of MHC class I (1). While inhibitory receptors expressing immunoreceptor tyrosine-based inhibition motifs prevent NK cells from harming tissues expressing normal levels of classical or nonclassical MHC class I (for a review , see reference 2), what turns on NK cells? Recent reports (3, 4), including Smith et al. in this issue (4), are beginning to unfold the receptors and signaling pathways involved in positive activation of NK cells. Unlike T cells or B cells, which recognize antigen using clonally restricted receptors generated by gene rearrangement , NK cells appear to use a variety of different, nonre-arranging receptors to initiate cytolytic activity and cyto-kine production (for a review, see reference 5). Many of these activating receptors are not restricted to NK cells; most are also present on T cells, and these serve as costimu-latory or adhesion receptors in both cell types. Like the ability of antibodies against CD3 or the T cell antigen receptor to trigger killing or cytokine production by cyto-toxic T cells, a productive strategy to search for activating NK cell receptors has involved screening for mAbs that initiate NK cell killing of Fc receptor–bearing tumor cell lines. Using this approach, several membrane receptors have been implicated in NK cell activation, including CD2 Expression of the ligands on target cells can initiate NK cell lysis or cytokine production , provided the NK cells are not turned off by inhibitory NK receptors recognizing class I molecules on the targets. Although several different activating NK cell receptors have been identified, many share a common adaptor molecule or signaling pathway. Recently, Pende et al. (3) reported that NKp30 lacks known signaling motifs in its cy-toplasmic domain, but noncovalently associates with CD3 ␨ to provide for cellular activation. CD16 also associates with CD3 ␨ (26), or the structurally similar Fc ⑀ RI ␥ chain (27, 28), and this receptor complex mediates antibody-dependent cellular cytotoxicity. NKp46 (29) and mouse NKR-P1 (30) are other NK cell receptors linked to CD3 ␨ or Fc ⑀ RI ␥ , respectively. Although not physically associated, CD3 ␨ has been implicated in CD2-mediated activation of NK cells (31). NK cells express both CD3 ␨ and Fc ⑀ RI ␥ , and these adaptor molecules form disulfide-bonded ho-modimers, as well as heterodimers with each other (28). CD3 ␨ and Fc ⑀ RI ␥ have immunoreceptor tyrosine-based activation motifs (ITAMs) …