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NK-Mediated Elimination of Mutant Lymphocytes that Have Lost Expression of MHC Class I Molecules¹

Yoichiro Kusunoki^2,*, Seishi Kyoizumi^*, Masamitsu Honma, Yoshiko Kubo^*, Hisashi Ohnishi^*, Tomonori Hayashi^* and Toshio Seyama^*

^* Department of Radiobiology, Radiation Effects Research Foundation, Hiroshima, Japan; and Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan

Mutant cells generated in vivo can be eliminated when mutated gene products are presented as altered MHC/peptide complexes and recognized by T cells. Diminished expression of MHC/peptide complexes enables mutant cells to escape recognition by T cells. In the present study, we tested the hypothesis that mutant lymphocytes lacking expression of MHC class I molecules are eliminated by autologous NK cells. In H-2^b/k F₁ mice, the frequency of H-2K^b-negative T cells was higher than that of H-2K^k-negative T cells. The frequency of H-2K-deficient T cells increased transiently after total body irradiation. During recovery from irradiation, H-2K^k-negative T cells disappeared more rapidly than H-2K^b-negative T cells. The disappearance of H-2K-deficient T cells was inhibited by administration of Ab against asialo-GM1. H-2K^k-negative T cells showed higher sensitivity to autologous NK cells in vitro than H-2K^b/k heterozygous or H-2K^b-negative T cells. Adding syngeneic NK cells to in vitro cultures prevented emergence of mutant cells lacking H-2K^k expression but had little effect on the emergence of mutant cells lacking H-2K^b expression. Results in the H-2^b/k F₁ strain correspond with the sensitivity of parental H-2-homozygous cells in models of marrow graft rejection. In H-2^b/d F₁ mice, there was no significant difference between the frequencies of H-2K^b-negative and H-2K^d-negative T cells, although the frequencies of mutant cells were different after radiation exposure among the strains examined. H-2^b/d F₁ mice also showed rapid disappearance of the mutant T cells after irradiation, and administration of Ab against asialo-GM1 inhibited the disappearance of H-2K-deficient T cells in H-2^b/d F₁ mice. Our results provide direct evidence that autologous NK cells eliminate mutant cell populations that have lost expression of self-MHC class I molecules.