A genetic defect in mice that impairs missing self recognition despite evidence for normal maturation and MHC class I-dependent education of NK cells.
In studies of a CD1d1-deficient mouse strain, we unexpectedly observed a severely impaired capacity for NK cell-mediated rejection of MHC class I-deficient (spleen or tumor) cells. Studies of another CD1-defective strain, as well as intercrosses with C57BL/6 mice, indicated that the impaired missing self rejection (IMSR) NK cell defect was a recessive trait, independent from the targeted CD1 locus. Studies with mixed bone marrow chimeras indicated that the defect is intrinsic to NK cells. The IMSR mice had normal proportions of NK cells, displaying a typical cell surface phenotype, as evaluated using a panel of Abs to developmental markers and known receptors. The impaired missing self recognition could not be overcome through cytokine stimulation. There was also an impaired capacity with respect to NKG2D-dependent cytotoxicity, whereas the mice exhibited normal Ly49D/DAP12-dependent responses in vivo and in vitro. The NK cell system of IMSR mice showed two hallmarks of MHC-dependent education: skewing of the Ly49 receptor repertoire and differential in vitro responsiveness between NK cells with and without inhibitory receptors for self-MHC ("licensing"). We conclude that these mice have a recessive trait that perturbs the missing self reaction, as well as NKG2D-dependent responses, whereas other aspects of the NK system, such as development, capacity to sense MHC molecules during education, and Ly49D/DAP12-dependent responses, are largely intact.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-17177 Stockholm, Sweden.
Stina L
SL
Wickström
Linda
L
Öberg
Klas
K
Kärre
Maria H
MH
Johansson
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D015395:Histocompatibility Antigens Class I; C527092:Klra4 protein, mouse; C527086:Klrk1 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; C484963:Tyrobp protein, mouse