Elimination of CD4+ CD25+ regulatory T cells breaks down reovirus type 2-triggered and CpG ODN-induced prolonged mild autoimmune insulitis in DBA/1 mice

Abstract

We have reported previously that subclinical prolonged mild T helper (Th) 1-dependent autoimmune insulitis with impaired glucose tolerance in wealing DBA/1J mice, which is induced by the combined effects of reovirus type 2 (Reo-2) and synthetic 20-base oligodeoxynucleotides with CpG motifs (CpG ODN) (control mice). Compared with the control mice, newborn mice treated with monoclonal antibody (MoAb) against mouse CD25(+) CD4(+) T cells together with Reo-2 and CpG ODN greatly reduced the absolute number of splenic CD25(+) T cells and resulted in the development of severe insulitis, leading to an overt early diabetes. Moreover, the treatment of the MoAb increased production of interferon-gamma (IFN-gamma) and decreased that of interleukin-4 (IL-4) and transforming growth factor-beta1 (TGF-beta1) and developed high titre of autoantibodies against pancreatic islet cells. These evidences suggest that CD4(+) CD25(+) T cell may, at least in part, maintain tolerance to Reo-2-triggered and CpG ODN-induced prolonged mild Th1-dependent autoimmune insulitis, leading to the overt disease. This system may give a novel model to elucidate the mechanisms of the development of overt diabetes from borderline subclinical diabetes in virus-triggered autoimmune type I diabetes in human.