Regulatory T cells protect from type 1 diabetes following induction by coxsackievirus infection in the context of TGF-β.

Abstract

Objective: Coxsackievirus infections have long been associated with the induction of type 1 diabetes (T1D). Infection with coxsackievirus B4 (CB4) enhances T1D onset in non-obese diabetic (NOD) mice by accelerating the presentation of β cell antigen to autoreactive T cells. It has been reported that a progressive defect in regulatory T cell (Treg) function is, in part, responsible for T1D onset in NOD mice. This defect may contribute to susceptibility to viral-induced T1D. We asked whether the immune response following CB4 infection could be manipulated in order to re-establish peripheral tolerance while maintaining the immune response to virus.

Research Design and Methods: NOD mice expressing 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 following CB4 infection in the presence of TGF-β prevented T1D. Interestingly, 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 T1D without altering the anti-viral response. Finally, when TGF-β was administered systemically to NOD mice post-infection the incidence of T1D 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 T1D without concomitant loss of the capacity to control viral infection.