Prevention of Allogeneic Bone Marrow Graft Rejection by H-2 Transgene in Donor Mice

Abstract

Rejection of bone marrow grafts in irradiated mice is mediated by natural killer (NK) cells and is controlled by genes linked to the major histocompatibility complex (MHC). It has, however, not been possible to identify the genes or their products. An MHC class I (Dd) transgene introduced in C57BL donors prevented the rejection of their bone marrow by NK cells in irradiated allogeneic and F1 hybrid mice expressing the Dd gene. Conversely, H-2Dd transgenic C57BL recipients acquired the ability to reject bone marrow from C57BL donors but not from H-2Dd transgenic C57BL donors. These results provide formal evidence that NK cells are part of a system capable of rejecting cells because they lack normal genes of the host type, in contrast to T cells, which recognize cells that contain abnormal or novel sequences of non-host type.

The First Molecular Basis of the “Missing Self” Hypothesis

“…In addition, the phenomenon of hybrid resistance, where a (A ϫ B)F 1 host rejects A or B grafts (A and B refers to MHC genotype), was known to be dependent on NK cells. Moreover, the notion that the absence of self-MHC expression seems to target cells for rejection was a strong suggestion that susceptibility to NK cell lysis of the parental graft was, at least in part, linked to the absence of specific MHC class I products in the donor (8,11). This observation supports the idea that NK cells recognize the absence of self.…”

“…Moreover, analysis by site-directed mutagenesis identified a residue in the peptide binding-groove that conferred susceptibility to NK cell lysis of HLA-A2-positive target cells (7). Further support for the "missing self" hypothesis was shown in manuscripts reporting that allogeneic bone marrow graft rejection could be prevented by expressing a H-2 transgene in donor mice (8), the rejection of class I MHCdeficient bone marrow cells by NK cells from MHC-matched mice (9), and the susceptibility of normal T cells from ␤ 2 -microglobulin deficient animals to normal NK cells (10). In addition, the phenomenon of hybrid resistance, where a (A ϫ B)F 1 host rejects A or B grafts (A and B refers to MHC genotype), was known to be dependent on NK cells.…”

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

“…First, there is a higher proportion of Ly49 ϩ NK cells in mice deficient in ␤ 2 -microblobulin (␤ 2 m) 3 compared with ␤ 2 m ϩ mice (39,40). Second, introducing an H-2D d transgene in B6 (H-2 b ) mice allowed specific subsets of NK cells to develop that were inhibited by H-2D d but not by H-2 b and, thus, rejected bone marrow transplants from B6 mice (41). Third, NK cells that express multiple H-2 d -specific Ly49 receptors are significantly less frequent in H-2 d mice compared with H-2 b mice (20).…”

Effect of Ly49 Haplotype Variance on NK Cell Function and Education

“…However, NK cells from b2m 2/2 or TAP 2/2 mice are not able to recognize MHC-I-deficient cells because MHC-I molecules are absent during NK cell development (9)(10)(11). In contrast, the ectopic expression of an H-2D d transgene in C57BL/6J (B6) mice facilitates rejection of wild-type (WT) B6 cells by transgenic NK cells as a result of the introduction of a novel self-MHC-I allele during NK cell education (12). Consistent with this, a greater number of educating self-MHC-I molecules in the host correlates with enhanced NK cell function upon exposure to MHC-I-deficient targets (13).…”