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

Abstract

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 (DC_OVA) 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 β cell destruction which led to diabetes in wild-type C57BL/6 mice and transgenic rat insulin promoter (RIP)-mOVA mice expressing β 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 DC_OVA by DC_OVA 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⁺ (K^b−/−) 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.