A natural killer cell receptor specific for a major histocompatibility complex class I molecule.

Abstract

Sllll~mal~Target cell expression of major histocompatibility complex (MHC) class I molecules correlates with resistance to lysis by natural killer (NK) cells. Prior functional studies of the murine NK cell surface molecule, Ly-49, suggested its role in downregulating NK cell cytotoxicity by specifically interacting with target cell H-2D d molecules. . Although the molecular basis for NK cell specificity is poorly understood, target cell susceptibility to spontaneous cytotoxicity is inversely proportional to their level of expression of certain MHC class I molecules (3-5). Two explanations (6) have been proposed. MHC class I molecules may "mask" or interfere with recognition of putative target cell ligands by activation receptors on NK cells. Alternatively, target cell MHC class I molecules may directly engage NK cell receptors leading to inhibitory events in NK ceils. Our previous functional studies (7) of the murine Ly-49 molecule have supported the latter hypothesis.Ly-49 is a type II integral membrane protein (8, 9), with an external C-type lectin domain (9), expressed on a distinct subset of murine NK cells (10) as a disulfide-linked homodimer of44-kD subunits (9). Functional studies with IL-2-activated NK cells demonstrated that Ly-49 + NK cells generally manifested a lytic capacity equivalent to Ly-49-NK cells (7). However, Ly-49 + NK cells were unable to lyse targets of H-2 k or H-2 d haplotype despite efficient lysis of these targets by Ly-49-NK cells, demonstrating that Ly-49 expression significantly influences NK cell target specificity. Transfection of a susceptible target cell line with cDNA encoding H-2D a rendered it resistant to lysis by Ly-49 + NK cells. Ly-49 + NK cells were unable to lyse the D a transfectant by other stimuli, including Ab-dependent cellular cytotoxicity (7, 11). Gene transferred resistance was abrogated by mAbs against either Ly-49 or the otl/o~2 domain of D a. These data were compatible with our hypothesis that Ly-49 is an inhibitory receptor that specifically recognizes D a molecules on targets.Our interpretation of t.hese functional studies predicts that Ly-49 directly interacts with H-2D d. Alternatively, the results may be explained by a NK cell surface molecule that is coexpressed with Ly-49 and that is indirectly influenced by the anti-Ly-49 mAb. Moreover, reversal of functional inhibition by mAbs could be due to other effects such as direct anti-Ly-49 triggering or anti-H-2D d dissociation of another effector cell ligand (12). A final possibility involves the "masking model" in which H-2D a masks another target molecule specifically recognized by . To distinguish between these possibilities, we sought to unequivocally establish the ligand for Ly-49. We have now overexpressed Ly-49 on Chinese hamster ovary (CHO) cells by transfection and DNA amplification. CHO cells bind target cells only when the cells express high levels of Ly-49 and H-2D a, respectively, by transfection. This interaction is specifically blocked by appropriate mAbs. Thus, this study demonstrates that...

The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2Dd Inside and Outside of the Peptide Binding Groove

“…Also, Ly49A expression on NK cells is modulated in mice expressing H-2D d (21). Physical interaction is supported by studies of Chinese hamster ovary cells transfected with Ly49A that bind H-2D d -transfected C1498 cells (22). The recognition of ␣1/␣2 domain of H-2D d is supported by two lines of indirect evidence.…”

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

“…Ly-49A binds the class I molecules H-2D d , D k , and D p , and Ly-49G2 binds H-2D d and H-2L d . [37][38][39][40][41] These bindings mediate a negative signal to the NK cells, resulting in inhibition of lysis. Recent studies have suggested that these members of the Ly-49 family may also interact with H-2 b molecules.…”

MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells

“…The inhibitory receptors contain an immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic tail that, upon receptor cross-linking, recruits Src homology 2 domaincontaining tyrosine phosphatase-1 and -2 (11)(12)(13)(14). Ly49A is the best characterized member and has been shown to recognize the class I molecules H-2D d , D k , and D p , and binding mediates a negative signal to the NK cell, resulting in inhibition of lysis (15)(16)(17).…”