TGF-β-induced TCR-Tg/NOD regulatory T cells suppress both autoimmune diabetes transfer and islet graft destruction in an antigen dependent manner (B75)

Abstract

Abstract Regulatory T cells (Tregs) are understood to fall into two categories: natural Tregs and induced Tregs. Induced Tregs can be produced by activating CD4 T cells in the presence of TGF-β. Such induced Tregs are of great promise for immunotherapy, but it has been unclear if they require stimulation by antigen in order to suppress in vivo. We have investigated the limits of induced Tregs in the NOD mouse model of type I diabetes. We produced TGF-β-induced Tregs from the 6.9 TCR-Tg/NOD mouse that are specific for islet autoantigen. In some experiments we used a congenic mouse, the NOD.C6, that specifically lacks the antigen for the 6.9 TCR-Tg T cells but not for other islet-specific T cells. These Tregs express Foxp3, and produce much less IFN-γ than non-Tregs. We have shown that induced Tregs can prevent transfer of diabetes by effector T cells in NOD mice, but fail to protect in NOD.C6 mice that lack the Treg antigen. These Tregs decrease inflammatory cytokine production and macrophage infiltration in the pancreas. In human patients with diabetes, induced Tregs might be used to protect islet grafts from immune destruction, and we have demonstrated that our induced Tregs can prevent islet graft destruction in NOD mice. In addition, we have grafted islets from the NOD.C6 mouse. By using these antigen-free islets, we have conclusively demonstrated that induced Tregs require activation by their antigen in the islet graft in order to protect.