Recognition of major histocompatibility complex class I antigens by natural killer cells

N 'atural Killer (NK) cells are cytotoxic lymphocytes that, in the absence of prior stimulation, lyse a variety of target cells, including tumor cells, virus-, or intracdlular bacteria-infected cells, and, in some cases, normal cells (1). Thus, NK cells represent a first line of defense to infections, tumor growth, or other pathogenic alterations of tissue homeostasis. Unlike T or B lymphocytes, NK cells do not express molecularly rearranged receptors and, in particular, neither rearrange nor express on their surface any of the four genes encoding the T cell receptor (TCR). Activation of NK cells results not only in cytotoxicity but also in rapid secretion of cytokines, particularly interferon-7 (IFN-3`), granulocyte/macrophage colony-stimulatory factor (GM-CSF), and tumor necrosis factor (TNF) (1). The ability of NK cells to recognize and destroy target cells has been considered nonspecific and possibly mediated by multiple adhesionlike receptors recognizing an altered pattern of expression of surface molecules on pathological target cells. The best characterized receptor able to activate NK cell cytotoxicity and cytokine production is the receptor for Fc of IgG type IliA (Fc3`RIIIA or CD16). CD16 is associated with dimers of the ~" chain of C D 3 / T C R or of the 3' chain of FceRI, and mediates signal transduction with similar mechanisms as those observed via the TCR/CD3 complex (1). Through CD16, NK cells recognize IgG antibody-coated target cells and mediate antibody-dependent cytotoxicity (ADCC). However, CD16 does not appear to be involved in the induction of cytotoxicity in the absence of antibodies (1). Other cytotoxicity-triggering receptors have been described on NK cells, but their ligands on target cells and their role in cytotoxicity have not been elucidated. Although the activity of NK cells has been considered nonspecific and, unlike CD8 § cytotoxic T lymphocytes (CTL), does not require the expression of major histocompatibility complex (MHC) antigens on target cells, evidence suggesting specificity in NK cell recognition has been accumulating for many years. Kiessling et al. (2) demonstrated that NK cells were the effector cells responsible for the rejection of parental bone marrow grafts in irradiated F1 mice (hematopoietic hybrid resistance) indicating a genetic specificity in NK cell action. The major locus responsible for this resistance, Hh-1, was mapped to the H-2DL region and studies with H-2D a transgenic mice strongly suggested that the product of the class I allele D d is a major determinant governing the genetic specificity of NK cells (3). In rats, NK cells rapidly eliminate in vivo allogeneic lymphocytes as well as bone marrow cells (allogeneic lymphocyte cytotoxicity, ALC), and aUoreactive NK calls were also generated in vitro (4). The genetic dements controlling this alloreactivity are in a dass I region (RT1-C) of the rat MHC, but, unlike routine hybrid resistance in which the susceptibility to rejection was always inherited as a recessive trait (and resistance as a dominant one), susceptibility to both rejection and lysis by rat alloreactive NK cells was found to segregate dominantly, although rarely, in some strain combinations (4). In several experimental systems, the susceptibility of target cells to NK call-mediated lysis is inversely proportional to their expression of class I MHC antigens (5). One of the hypotheses to explain the ability of NK cells to recognize class I low target cells is the "missing self hypothesis" that postulates that one function of NK cells is to recognize and eliminate cells that do not express MHC class I molecules (5). This hypothesis needs to be modified, however, to accommodate findings suggesting that NK cells may be affected not only by the presence or absence of class I molecules, but also by the nature of MHC-bound peptide fitting, either because, similarly to T cells, they might directly sense the combination of peptide and MHC, or because they recognize changes in molecular conformations of the MHC molecules induced by the peptide binding (6). The peptide-binding class I o~1/o~2 domains have been shown to be necessary for NK cell recognition, and single amino acid substitutions in the peptide-binding groove of the class I molecules alter the ability of the molecules to protect target cdls from NK cells (6). It has also been suggested that alteration of endogenous peptides by external peptide loading or by virus infection abrogates class I-mediated resistance of target cells and makes them susceptible to NK cdl cytotoxicity (7). Two hypotheses have been proposed to explain the mechanism of dass I recognition by NK cells: (a) the effector inhibition hypothesis postulating that the presence of class I (or particular conformations of class I) on the target ceUs ddivers a negative signal to the NK cells, which prevents the activation of cytotoxicity; or (b) the target interference hypothesis postulating that class I antigens or their peptides sterically mask recognition of an NK target structure on the target cells (5). Although many of the experimental data can be explained on the basis of either hypothesis, or through intermediate interpretations, several recent lines of evidence, discussed below, appear to favor the effector inhibition hypothesis. The first receptor identified on murine NK cells that is probably involved in recognition of class I MHC is the Ly-49