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The Journal of Immunology, 2000, 164: 3913-3918.
Copyright © 2000 by The American Association of Immunologists

Identification of a CD8 T Cell That Can Independently Mediate Autoimmune Diabetes Development in the Complete Absence of CD4 T Cell Helper Functions1

Robert T. Graser*, Teresa P. DiLorenzo{dagger}, Fuming Wang2,{ddagger}, Gregory J. Christianson*, Harold D. Chapman*, Derry C. Roopenian*, Stanley G. Nathenson{dagger},{ddagger} and David V. Serreze3,*

* The Jackson Laboratory, Bar Harbor, ME 04609; and Departments of {dagger} Microbiology and Immunology and {ddagger} 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{alpha}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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