Acquired pMHC I Complexes Greatly Enhance CD4+ Th Cell's Stimulatory Effect on CD8+ T Cell-Mediated Diabetes in Transgenic RIP-mOVA Mice

CD4(+) helper T (Th) cells play pivotal roles in induction of CD8(+) CTL immunity. However, the mechanism of CD4(+) T cell help delivery to CD8(+) T cells in vivo is still elusive. In this study, we used ovalbumin (OVA)-pulsed dendritic cells (DCOVA) to activate OT-II mouse CD4(+) T cells, and then studied the help effect of these CD4(+) T cells on CD8(+) cytotoxic T lymphocyte (CTL) responses. We also examined CTL mediated islet beta cell destruction which leaded to diabetes in wild-type C57BL/6 mice and transgenic rat insulin promoter (RIP)-mOVA mice expressing beta cell antigen OVA with self OVA-specific tolerance, respectively. In adoptive transfer experiments, we demonstrated that help, in the form of peptide/major histocompatibility complex (pMHC) I acquired from DCOVA by DCOVA activation, was required for induction of OVA-specific CTL responses in C57BL/6 mice. However, in combination with TCR transgenic OT-I mouse CD8+ T cells, the tolerogenic dosage of CD4+ Th cells with acquired pMHC I, but not CD4(+) (Kb-/-) Th cells without acquired pMHC I were able to cause diabetes in 8/10 (80%) RIP-mOVA mice. This study thus expands the current knowledge in T cell-mediated autoimmunity and provides insight into the nature of CD4(+) T cell-mediated help in CD8(+) CTL induction. Cellular & Molecular Immunology. 2008;5(6):407-415.