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Sections of Infectious Diseases and Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Nonobese diabetic (NOD) mice develop spontaneous autoimmune
diabetes that involves participation of both CD4+ and
CD8+ T cells. Previous studies have demonstrated
spontaneous reactivity to self-Ags within the CD4+ T cell
compartment in this strain. Whether CD8+ 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
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+ 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+ T cell repertoire of NOD-InsHA mice. CD8+
T cells can be obtained from NOD-InsHA mice that exhibit high avidity
for HA, as measured by tetramer (KdHA) binding and dose
titration analysis. Significantly, these autoreactive CD8+
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+ T cells with high avidity for islet
Ags that could contribute to autoimmune diabetes in NOD
mice.
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