Authors: Michael S Turner Kumiko Isse Douglas K Fischer Hēth R Turnquist Penelope A Morel
Publish Date: 2014/04/16
Volume: 57, Issue: 7, Pages: 1428-1436
Abstract
Weak stimulation of CD4+ T cells induces expansion of CD4+ forkhead box P3+ regulatory T cells Tregs and can also promote T helper Th 2 responses which have demonstrable beneficial effects on autoimmune diabetes This study explored the feasibility of combined Treg/Th2 expansion for immunotherapy of type 1 diabetes in NOD miceWe compared Treg and Th responses to dendritic cells DC presenting scaled antigen doses to isletspecific NOD CD4+ T cells Flow cytometric and Luminex analyses were performed to determine the phenotype and cytokine profile of expanded T cells The ability of expanded T cells to prevent type 1 diabetes was tested in an adoptive transfer modelIn vitro studies revealed a hierarchical selective expansion of Treg and T effector Teff populations at different antigen doses Thus a single low dose produced a mixture of Tregs Th2 and type 1 regulatory Tr1 cells which prevented diabetes in NODSCID mice and increased the ratio of Treg/Teff cells infiltrating the pancreatic islets Subcutaneous injection of DC previously shown to prevent diabetes in NOD mice induced expansion of the same mixture of Tregs Tr1 and Th2 cells Lowdose expansion of Treg required MHC–T cell receptor interaction and was partly dependent on T cell derived TGFβ and IL2 Autocrine IFNγ was required for the promotion of diabetogenic Th1 cells at high antigen doses
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