Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions

Previous work has indicated that an important component for the initiation of autoimmune insulin-dependent diabetes mellitus (IDDM) in the NOD mouse m odel entails MHC class I-restricted CDS T cell responses against pancreatic P cell Ags, However, unless previously activated in vitro, such CD8 T cell s have previously been thought to require helper functions provided by MHC class II-restricted CD4 T cells to exert their full diabetogenic effects. I n this study, we show that IDDM development is greatly accelerated in a sto ck of NOD mice expressing TCR transgenes derived from a MHC class I-restric ted CD8 T cell clone (designated AI4) previously found to contribute to the earliest preclinical stages of pancreatic beta cell destruction, Important ly, these TCR transgenic NOD mice (designated NOD.AI4 alpha beta Tg) contin ued to develop IDDM at a greatly accelerated rate when residual CD4 helper T cells were eliminated by introduction of the scid mutation or a functiona lly inactivated CD4 allele, In a previously described stock of NOD mice exp ressing TCR transgenes derived from another MHC class I-restricted beta cel l autoreactive T cell clone, IDDM development was retarded by elimination o f residual CD4 T cells. Hence, there is variability in the helper dependenc e of CD8 T cells contributing to the development of autoimmune IDDM. The AI 4 clonotype represents the first CD8 T cell with a demonstrated ability to progress from a naive to functionality activated state and rapidly mediate autoimmune IDDM development in the complete absence of CD4 T cell helper fu nctions.