The ability of natural killer (NK) cells to eliminate normal allogeneic hemic cells is well established in several species including mice, rats, and humans. The controlling elements for NK susceptibility in these species map to the major histocompatibility complex (MHC), but in contrast to findings in mice and humans, the mode of inheritance is not always recessive in rats. This finding is not easily explained by the missing self and hemopoietic histocompatibility (Hh) models for NK recognition, and has led to the idea that certain aUoantigens may trigger NK cell reactivity. In our in vitro system for assessing rat NK alloreactivity, we have employed target and inhibitor cells from a large panel ofMHC congenic, intra-MHC recombinant and MHC mutant rat strains, as well as appropriate F1 hybrids between them, and we show the following: (a) The nonclassical class I (RT/.C) region was most important in determining the susceptibility of target cells to alloreactive NK cells in vitro. Lymphocyte susceptibility to lysis in vivo also mapped to the C region, which supports the concept that the in vivo and in vitro alloreactivity assays reflect the same recognition process. (b) Four different RT/-controlled NK allospecificities (represented by the u, l, a, and n haplotypes) could be discerned when we used polyclonal NK cells from the PVG (RTI') strain as effector cells. Three of the target specificities recognized were controlled mainly by the RT1.C region. (c) The expression of RT1.C region-controlled parental strain NK allodeterminants could be demonstrated in F1 hybrids heterozygous for the C region alone and were therefore inherited nonrecessively. (d) Loss of an RTI.C region-controlled NK allospecificity could be shown with the MHC mutant LEW.1LM1 rat strain characterized by a genomic deletion of about 100 kb of the C region. Taken together, these observations have demonstrated a major importance of the nonclassical class I region, i.e., RT1.C, in controlling rat NK allorecognition, and have thereby assigned a hitherto undescribed immunological property to this region. Furthermore, some of the present data are consistent with the existence of polymorphic NKtriggering alloantigens that are coded for by the RT1.C region.

A major role for the nonclassical major histocompatibility complex (MHC) class I region, i.e. RT1.C, in controlling rat natural killer (NK) cell alloreactivity has recently been established, and several findings suggested the existence of NK-triggering alloantigens coded for by this region. Here, we have extended our studies on the MHC control of NK cell cytotoxicity against concanavalin A-activated T cell blasts by comparing semi-syngeneic and fully allogeneic combinations, and we show the following: (a) The self MHC exerted a strong influence on the NK allorecognition repertoire. (b) When anti-F1 hybrid cytolytic activities of parental strain NK cells were measured, both recessively and non-recessively inherited susceptibility patterns emerged. (c) In most combinations parental strain cells were lysed by F1 hybrid NK cells, thus resembling the hybrid resistance phenomenon described in mice. The cytotoxicity was lower in strain combinations where NK susceptibility was inherited non-recessively, i.e. when parent anti-F1 reactivity was detected, than in recessive combinations. (d) LEW.1LM1 (RT1lm1) target cells, with a deletion in the RT1.C region that includes expressed class I genes, were more sensitive to lysis by MHC matched NK cells (PVG.1L(LEW), RT1l) than were parental LEW (RT1l) cells. The effect of the deletion was the opposite when MHC allogeneic (RT1c, RT1u) as well as semi-syngeneic (RT1l/c) NK cells were employed, i.e. sensitivity was decreased. We conclude that certain MHC-encoded antigens, depending on the haplotype combination of effector and target cells, may either trigger or inhibit rat NK cell cytotoxicity. Furthermore, the potential role of peptides bound to MHC class I molecules recognized by NK cells is discussed.

The prompt rejection of transplanted allogeneic lymphocytes by rat NK cells in non-sensitized recipients (allogeneic lymphocyte cytotoxicity or ALC) is determined by MHC genes as well as by genes located in the NK complex. The same genetic control is found when NK alloreactivity is measured by an in vitro assay, and we have employed this assay to delineate the specificity of NK cells for the MHC. The MHC of the rat, RT1, contains class I genes situated on either side of the class II/class III region. The majority of these class I genes are located in the RT1.C region and expressed class I products usually behave as non-classical (class Ib) molecules. They do not serve as restriction elements for the vast majority of conventional alpha/beta T-cells, in contrast to those class I molecules encoded by one or more loci in the classical (class Ia) region, RT1.A. However, NK cells appear to recognize the products of either class I region. Immunogenetic studies suggest that NK cells are inhibited by RT1. A molecules, whereas RT1.C region molecules may have a dual role in regulating NK cytolytic activity, i.e. they either inhibit or activate natural killing. Based on these premises, a model is proposed in which identification of a target as self or non-self depends on different receptors for class I in single NK cells, interpreting coincident positive and negative signals from the various target class I molecules. The putative role of peptides presented by class I, the biological implications, and the evolution of the NK receptors and their ligands are discussed.