Most recently, a completely new subset of NK cells with immunosuppressive functions has been identified. These cells are able to downregulate conventional NK cells in a PD1-ligand dependent manner and are, therefore, responsible for tumor outgrowth.
The aim of our present study was to investigate the role of this new NK subset in autoimmunity. For this purpose, we used two independent mouse models. In the NOD mice, we found a large increase of suppressive NK cells at 8 weeks of age, a time point when strong T cell infiltrations are detected in pancreatic islets. Besides, we used an alternative T1DM mouse model for detailed analyses by the multiple administration of low-dose streptozotozin (STZ). We detected an increase of suppressive NK cells in the pancreas of STZ-mice within the days after application of the antibiotic. At that time mice have still relatively low levels of blood glucose in contrast to those, who developed diabetes within day 10 to 21 after first STZ administration. In vitro, we showed that these cells havent only a direct lysis activity towards conventional NK cells but also towards activated CD8+ T cells and primed insulin beta-chain specific CD8+ T cells for more than 40%. While the immunosuppressive NK cells can be generated by IL-18 over night we performed an adoptive cell transfer by systemic repetitive injections. In vivo, we were able to delay the normal increase of blood glucose after STZ in 40% of mice treated with immunosuppressive NK cells. These animals were still alive at week 20 with only a mild form of T1DM. In contrast, all mice which received conventional NK cells did not survive week 14.
This is the first report describing the role of immunosuppressive NK cells in autoimmunity proving a direct link between innate immunity and adapted immunity in T1DM.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology