Defective CD8(+) T cell peripheral tolerance in nonobese diabetic mice

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that i nvolves participation of both CD4(+) and CD8(+) T cells. Previous studies h ave demonstrated spontaneous reactivity to self-Ags within the CD4+ T cell compartment in this strain. Whether CDS' T cells in NOD mice achieve and ma intain tolerance to self-Ags has not previously been evaluated. To investig ate this issue, we have assessed the extent of tolerance to a model pancrea tic Ag, the hemagglutinin (HA) molecule of influenza virus, that is transge nically expressed by pancreatic islet beta cells in InsHA mice. Previous st udies have demonstrated that BALB/c and MOM mice that express this transgen e exhibit tolerance of HA and retain only low-avidity CD8(+) T cells specif ic for the dominant peptide epitope of HA. In this study, we present data t hat demonstrate a deficiency in peripheral tolerance within the CDS' T cell repertoire of NOD-InsHA mice. CD8(+) T cells can be obtained from NOD-InsH A mice that exhibit high avidity for HA, as measured by tetramer (K(d)HA) b inding and dose titration analysis. Significantly, these autoreactive CD8() T cells can cause diabetes very rapidly upon adoptive transfer into NOD-I nsHA recipient mice. The data presented demonstrate a retention in the repe rtoire of CD8(+) T cells with high avidity for islet Ags that could contrib ute to autoimmune diabetes in NOD mice.