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Natural killer cell tolerance in mice with mosaic expression of major histocompatibility complex class I transgene.

Johansson MH, Bieberich C, Jay G, Kärre K, Höglund P - J. Exp. Med. (1997)

Bottom Line: The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another.We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand.Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

View Article: PubMed Central - PubMed

Affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.

ABSTRACT
We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

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In vitro cytotoxicity of IL-2–activated NK cells. IL-2–activated NK cells from B6 (circles), DL1 (diamonds), and DL6 (squares) mice  were tested in a chromium release assay using lymphoblasts from B6,  DL1, and β2m−/− mice as target cells. Target cells are indicated in the upper right corner of each graph. The figure shows one experiment out of  three with similar results.
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Figure 4: In vitro cytotoxicity of IL-2–activated NK cells. IL-2–activated NK cells from B6 (circles), DL1 (diamonds), and DL6 (squares) mice were tested in a chromium release assay using lymphoblasts from B6, DL1, and β2m−/− mice as target cells. Target cells are indicated in the upper right corner of each graph. The figure shows one experiment out of three with similar results.

Mentions: To test the ability of NK cells in Dd/Ld-transgenic mice to reject H-2b–positive but Dd/Ld–negative lymphoma cells, RMA tumor cells (of B6 origin) were inoculated subcutaneously into DL6, DL1, B6, and D8 mice (Table 2). In contrast with D8 and DL1 mice, which both resisted the tumor, mosaic DL6 mice all developed large tumors within 2 wk after inoculation. This was also the case with anti-NK1.1–treated DL1 and D8 mice and with nontransgenic B6 mice. The failure of DL6 mice to reject RMA tumor cells was not related to the number of Dd/Ld-positive cells in the mosaic mice; animals with 80% positive cells were as susceptible to tumor growth as those with 18% positive cells (included in Table 2). This finding argues against the possibility that the mosaic mice have too few Dd/Ld-positive NK cells to eliminate transgene-negative cells. The fact that the mice failed to reject even a low dose of tumor cells also speaks against this alternative (Table 2). Mosaic DL6 mice were also unable to reject bone marrow grafts of the H-2b haplotype (Fig. 3 A), and IL-2–activated NK cells from DL6 mice failed to kill B6-derived lymphoblasts in vitro (Fig. 4). In contrast, NK cells from DL1 mice rejected H-2b bone marrow grafts in vivo (see Fig. 3) and killed B6-derived lymphoblasts in vitro (Fig. 4). Thus, they behaved as transgenic mice expressing a normal Dd transgene (15, 17).


Natural killer cell tolerance in mice with mosaic expression of major histocompatibility complex class I transgene.

Johansson MH, Bieberich C, Jay G, Kärre K, Höglund P - J. Exp. Med. (1997)

In vitro cytotoxicity of IL-2–activated NK cells. IL-2–activated NK cells from B6 (circles), DL1 (diamonds), and DL6 (squares) mice  were tested in a chromium release assay using lymphoblasts from B6,  DL1, and β2m−/− mice as target cells. Target cells are indicated in the upper right corner of each graph. The figure shows one experiment out of  three with similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199002&req=5

Figure 4: In vitro cytotoxicity of IL-2–activated NK cells. IL-2–activated NK cells from B6 (circles), DL1 (diamonds), and DL6 (squares) mice were tested in a chromium release assay using lymphoblasts from B6, DL1, and β2m−/− mice as target cells. Target cells are indicated in the upper right corner of each graph. The figure shows one experiment out of three with similar results.
Mentions: To test the ability of NK cells in Dd/Ld-transgenic mice to reject H-2b–positive but Dd/Ld–negative lymphoma cells, RMA tumor cells (of B6 origin) were inoculated subcutaneously into DL6, DL1, B6, and D8 mice (Table 2). In contrast with D8 and DL1 mice, which both resisted the tumor, mosaic DL6 mice all developed large tumors within 2 wk after inoculation. This was also the case with anti-NK1.1–treated DL1 and D8 mice and with nontransgenic B6 mice. The failure of DL6 mice to reject RMA tumor cells was not related to the number of Dd/Ld-positive cells in the mosaic mice; animals with 80% positive cells were as susceptible to tumor growth as those with 18% positive cells (included in Table 2). This finding argues against the possibility that the mosaic mice have too few Dd/Ld-positive NK cells to eliminate transgene-negative cells. The fact that the mice failed to reject even a low dose of tumor cells also speaks against this alternative (Table 2). Mosaic DL6 mice were also unable to reject bone marrow grafts of the H-2b haplotype (Fig. 3 A), and IL-2–activated NK cells from DL6 mice failed to kill B6-derived lymphoblasts in vitro (Fig. 4). In contrast, NK cells from DL1 mice rejected H-2b bone marrow grafts in vivo (see Fig. 3) and killed B6-derived lymphoblasts in vitro (Fig. 4). Thus, they behaved as transgenic mice expressing a normal Dd transgene (15, 17).

Bottom Line: The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another.We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand.Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

View Article: PubMed Central - PubMed

Affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.

ABSTRACT
We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

Show MeSH
Related in: MedlinePlus