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,
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The Jackson Laboratory, Bar Harbor, ME 04609; and Departments of
Microbiology and Immunology and
Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Previous work has indicated that an important component for the
initiation of autoimmune insulin-dependent diabetes mellitus (IDDM) in
the NOD mouse model entails MHC class I-restricted CD8 T cell responses
against pancreatic ß cell Ags. However, unless previously activated
in vitro, such CD8 T cells have previously been thought to require
helper functions provided by MHC class II-restricted CD4 T cells to
exert their full diabetogenic effects. In this study, we show that IDDM
development is greatly accelerated in a stock of NOD mice expressing
TCR transgenes derived from a MHC class I-restricted CD8 T cell clone
(designated AI4) previously found to contribute to the earliest
preclinical stages of pancreatic ß cell destruction. Importantly,
these TCR transgenic NOD mice (designated NOD.AI4
ß Tg) continued
to develop IDDM at a greatly accelerated rate when residual CD4 helper
T cells were eliminated by introduction of the scid
mutation or a functionally inactivated CD4 allele. In a
previously described stock of NOD mice expressing TCR transgenes
derived from another MHC class I-restricted ß cell autoreactive T
cell clone, IDDM development was retarded by elimination of residual
CD4 T cells. Hence, there is variability in the helper dependence of
CD8 T cells contributing to the development of autoimmune IDDM. The AI4
clonotype represents the first CD8 T cell with a demonstrated ability
to progress from a naive to functionally activated state and rapidly
mediate autoimmune IDDM development in the complete absence of CD4 T
cell helper functions.
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