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


METHODS
NOD mice expressing transforming growth factor-beta (TGF-beta) specifically in the beta-cells were infected with CB4, and the functional role of Tregs in disease protection was measured. Systemic treatments with TGF-beta were used to assess its therapeutic potential.


RESULTS
Here, we report that Tregs induced after CB4 infection in the presence of TGF-beta prevented type 1 diabetes. The capacity to directly infect pancreatic beta-cells correlated with increased numbers of pancreatic Tregs, suggesting that presentation of beta-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-beta was administered systemically to NOD mice after infection, the incidence of type 1 diabetes was reduced, thereby signifying a potential therapeutic role for TGF-beta.


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.
Richer
Martin J
MJ
Department of Microbiology and Immunology, The University of British Columbia, 3551-2350 Health Sciences Mall, Vancouver, BC, Canada.
Straka
Nadine
N
Fang
Dianne
D
Shanina
Iryna
I
Horwitz
Marc S
MS
D000818:Animals; D003384:Coxsackievirus Infections / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000276:immunology* / Q000821:virology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta