Minute defects in the expression of MHC E molecules lead to impaired protection from autoimmunity in NOD mice

The E complex of the major histocompatibility complex (MHC) can prevent the spontaneous development of diabetes in nonobese diabetic (NOD) mice transg enic for the Ea gene. None of three promoter-mutated Ea constructs with Ea expression directed to different subsets of immunocompetent cells exerts fu ll protection in NOD mice. The promoter-mutated constructs are all capable of mediating intrathymic elimination of I-E restricted T cells, Thus, thymi c negative selection is not responsible for the protective effect but a mor e complex effect is likely. Here we show that combinations of two or three different mutated Ea constructs do not protect against intra-islet insuliti s either. We also show that spleen cells from protected animals are suffici ent to protect NOD mice in adoptive transfer experiments, The only detectab le expression defects in splenic cells or cells influencing the repertoire of splenic cells are in the B-cell compartment. Furthermore, in three const ruct combinations, the differences to wild-type expression are extremely sm all. Thus, we conclude that even minute disturbances of the E expression pa ttern might reduce the protection of NOD mice from insulitis.