Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-β

Abstract

OBJECTIVE-Coxsackievirus infections have long been associated with the induction of type 1 diabetes. Infection with coxsackievirus B4 (CB4) enhances type 1 diabetes onset in NOD mice by accelerating the presentation of β-cell antigen to auto-reactive T-cells. It has been reported that a progressive defect in regulatory T-cell (Treg) function is, in part, responsible for type 1 diabetes onset in NOD mice. This defect may contribute to susceptibility to viral-induced type 1 diabetes. We asked whether the immune response after CB4 infection could be manipulated to reestablish peripheral tolerance while maintaining the immune response to virus. RESEARCH DESIGN AND METHODS-NOD mice expressing transforming growth factor-β (TGF-β) specifically in the β-cells were infected with CB4, and the functional role of Tregs in disease protection was measured. Systemic treatments with TGF-β were used to assess its therapeutic potential. RESULTS-Here, we report that Tregs induced after CB4 infection in the presence of TGF-β prevented type 1 diabetes. The capacity to directly infect pancreatic β-cells correlated with increased numbers of pancreatic Tregs, suggesting that presentation of β-cell antigen is integral to induction of diabetogenic protective Tregs. Furthermore, the presence of these viral induced Tregs correlated with protection from type 1 diabetes without altering the antiviral response. Finally, when TGF-β was administered systemically to NOD mice after infection, the incidence of type 1 diabetes was reduced, thereby signifying a potential therapeutic role for TGF-β. CONCLUSIONS-We demonstrate manipulations of the immune response that result in Treg-mediated protection from type 1 diabetes without concomitant loss of the capacity to control viral infection. © 2008 by the American Diabetes Association.