The basis for self-tolerance of natural killer cells in beta2-microglobulin- and TAP-1- mice.
Cells from mice with mutations in the genes for beta2-microglobulin (beta2m) or for TAP-1 express only low levels of MHC class I proteins on their surfaces, and are thus sensitive to attack by normal NK cells. Although NK cells are present in beta2m- mice and TAP-1(-) mice, they are completely self-tolerant. The underlying mechanism for this tolerance is unknown. It has been proposed that education processes render NK cells from these mice hypersensitive to class I-mediated inhibition, so that they can be inhibited even by the low levels of class I expressed on autologous cells. In this study, we present evidence against this hypothesis, by demonstrating that NK cells from beta2m- mice and TAP-1(-) mice fail to attack beta2m(-)TAP-1(-) double-mutant cells in both in vitro and in vivo assays. The latter cells express substantially lower levels of class I than single-mutant cells, based on serologic tests, as well as a significantly diminished sensitivity to attack by class I-specific CTL. Furthermore, the Ly-49 repertoire on NK cells derived from beta2m(-)TAP-1(-) mice is highly similar to that of either single mutant, indicating that the developmental processes that shape the Ly-49 repertoire cannot respond to the differences in class I levels among these mice. We propose that self-tolerance of NK cells in beta2m- mice and TAP-1(-) mice is likely to result from hyporesponsiveness of the cells to activating signals, or alternatively, to induction of inhibitory signaling through receptors specific for non-class I MHC ligands.
Dorfman
J R
JR
Department of Molecular and Cell Biology & Cancer Research Laboratory, University of California at Berkeley, 94720, USA.
Zerrahn
J
J
Coles
M C
MC
Raulet
D H
DH
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000950:Antigens, Ly / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006085:Graft Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017634:Self Tolerance; D001613:beta 2-Microglobulin / Q000235:genetics*
D000950:Antigens, Ly; D016326:Extracellular Matrix Proteins; D015395:Histocompatibility Antigens Class I; D009419:Nerve Tissue Proteins; D001613:beta 2-Microglobulin