Defective CD8 super(+) T Cell Peripheral Tolerance in Nonobese Diabetic Mice

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that involves participation of both CD4 super(+) and CD8 super(+) T cells. Previous studies have demonstrated spontaneous reactivity to self-Ags within the CD4 super(+) T cell compartment in this strain. Whether CD8 super(+) T cells in NOD mice achieve and maintain tolerance to self-Ags has not previously been evaluated. To investigate this issue, we have assessed the extent of tolerance to a model pancreatic Ag, the hemagglutinin (HA) molecule of influenza virus, that is transgenically expressed by pancreatic islet beta cells in InsHA mice. Previous studies have demonstrated that BALB/c and B10.D2 mice that express this transgene exhibit tolerance of HA and retain only low-avidity CD8 super(+) T cells specific for the dominant peptide epitope of HA. In this study, we present data that demonstrate a deficiency in peripheral tolerance within the CD8 super(+) T cell repertoire of NOD-InsHA mice. CD8 super(+) T cells can be obtained from NOD-InsHA mice that exhibit high avidity for HA, as measured by tetramer (K super(d)HA) binding and dose titration analysis. Significantly, these autoreactive CD8 super(+) T cells can cause diabetes very rapidly upon adoptive transfer into NOD-InsHA recipient mice. The data presented demonstrate a retention in the repertoire of CD8 super(+) T cells with high avidity for islet Ags that could contribute to autoimmune diabetes in NOD mice.