title: Differential Role of Hematopoietic and Nonhematopoietic Cell Types in the Regulation of NK Cell Tolerance and Responsiveness.
abstract: Many NK cells express inhibitory receptors that bind self-MHC class I (MHC I) molecules and prevent killing of self-cells, while enabling killing of MHC I-deficient cells. But tolerance also occurs for NK cells that lack inhibitory receptors for self-MHC I, and for all NK cells in MHC I-deficient animals. In both cases, NK cells are unresponsive to MHC I-deficient cells and hyporesponsive when stimulated through activating receptors, suggesting that hyporesponsiveness is responsible for self-tolerance. We generated irradiation chimeras, or carried out adoptive transfers, with wild-type (WT) and/or MHC I-deficient hematopoietic cells in WT or MHC I-deficient C57BL/6 host mice. Unexpectedly, in WT hosts, donor MHC I-deficient hematopoietic cells failed to induce hyporesponsiveness to activating receptor stimulation, but did induce tolerance to MHC I-deficient grafts. Therefore, these two properties of NK cells are separable. Both tolerance and hyporesponsiveness occurred when the host was MHC I deficient. Interestingly, infections of mice or exposure to inflammatory cytokines reversed the tolerance of NK cells that was induced by MHC I-deficient hematopoietic cells, but not the tolerance induced by MHC I-deficient nonhematopoietic cells. These data have implications for successful bone marrow transplantation, and suggest that tolerance induced by hematopoietic cells versus nonhematopoietic cells may be imposed by distinct mechanisms.
authors: Department of Molecular and Cell Biology, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
authors: Nataliya Tovbis
authors: NT
authors: Shifrin
authors: Department of Molecular and Cell Biology, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
authors: Djem U
authors: DU
authors: Kissiov
authors: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada and Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors: Michele
authors: M
authors: Ardolino
authors: Department of Molecular and Cell Biology, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
authors: Nathalie T
authors: NT
authors: Joncker
authors: Department of Molecular and Cell Biology, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
authors: David H
authors: DH
authors: Raulet
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology* / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D017634:Self Tolerance
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I