Broadly impaired NK cell function in non-obese diabetic mice is partially restored by NK cell activation in vivo and by IL-12/IL-18 in vitro.
NK cells represent a link between innate and adaptive immunity, and may play a role in regulating autoimmune disorders. We have characterized the NK cell population in non-obese diabetic (NOD) mice. The percentage and absolute numbers of NK cells were similar in NOD and control MHC-matched B6.g7 mice. However, the capacity of NOD NK cells to mediate natural cytotoxicity as well as FcR- and Ly49D-mediated killing was compromised in vitro, suggesting a defect affecting multiple activation pathways. The defect was neither linked to the NK gene complex nor to the MHC, as determined by comparison with mice congenic for these regions. Introducing the beta(2)-microglobulin mutation on the NOD background further impaired NK cell function, showing that the compromised cytotoxic capacity in these two strains arises from two independent mechanisms. In vivo rejection responses against tumor cells and against MHC class I-deficient spleen cells were decreased in naive NOD recipients, but restored in mice pre-activated with tilorone, a potent activator of NK cells. In addition, killing of some tumor targets was restored in vitro after activation of NK cells with IL-12 plus IL-18 or with IFN-alpha/beta, but not with IL-2. Interestingly, natural killing of RMA-S targets by NOD NK cells could not be restored in vitro, indicating that restoration of killing capacity was only partial. Our data suggest a severe, but partially restorable, killing defect in NOD NK cells, affecting activation through several pathways.
Johansson
Sofia E
SE
Microbiology and Tumor Biology Center, Karolinska Institutet, 17 177 Stockholm, Sweden.
Hall
Håkan
H
Björklund
Jens
J
Höglund
Petter
P
D000818:Animals; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D001613:beta 2-Microglobulin / Q000235:genetics
D020382:Interleukin-18; D001613:beta 2-Microglobulin; D018664:Interleukin-12