The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/8/353/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 3, August 4, 1997 353-364

Articles

Natural Killer Cell Tolerance in Mice with Mosaic Expression of Major Histocompatibility Complex Class I Transgene

Maria H. Johansson*, Charles Bieberich{ddagger}, Gilbert Jay{ddagger}, Klas Kärre*, and Petter Höglund*

From the * Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden; and the {ddagger} Department of Virology, Jerome H. Holland Laboratory, Rockville, Maryland 28255

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.

Address correspondence to Petter Höglund, Microbiology and Tumor Biology Center (MTC), Karolinska Institute, Box 280, S-171 77 Stockholm, Sweden. Phone: 46-8-728-6768; FAX: 46-8-30-64-38; E-mail: Petter.Hoglund{at}mtc.ki.se

1 Abbreviations used in this paper: BMC, bone marrow cells; MPC, magnetic particle concentrator.


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