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Regulatory T-Cells Protect From Type 1 Diabetes After Induction by Coxsackievirus Infection in the Context of Transforming Growth Factor-β

From the Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada

Corresponding author: Marc S. Horwitz, Department of Microbiology and Immunology, The University of British Columbia, 3551-2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. E-mail: mhorwitz{at}interchange.ubc.ca

Abbreviations: APC, antigen-presenting cell; CB4, coxsackievirus B4; CIHR, Canadian Institutes of Health Research; DMEM, Dulbecco's modified Eagle's medium; H-E, hematoxylin-eosin; IFN-, -interferon; IL, interleukin; MSFHR, Michael Smith Foundation for Health Research; PFU, plaque-forming unit; PLN, pancreatic lymph node; TGF-β, transforming growth factor-β; TNF-, tumor necrosis factor-; Treg, regulatory T-cell

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 autoreactive 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.

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