Can We Learn From Viruses How to Prevent Type 1 Diabetes?: Prevention of Type 1 Diabetes Through Viral Infections

Prevention of Type 1 Diabetes Through Viral Infections

What about the flipside of this coin, that is, the possibility that viral infections and other types of infectious diseases would actually prevent type 1 diabetes? At first, this seems counterintuitive because of the aforementioned data indicating that viruses can be strong inducers of inflammation. However, emerging experimental evidence from various animal models has taught us otherwise. I will discuss some of the evidence and underlying mechanisms in the following examples.

New unpublished data from us and published work from others[37-39] support the so-called “hygiene hypothesis,” which implies that type 1 diabetes is a disease of the more industrialized countries because lesser numbers of infections occur and the immune system has therefore less opportunity to be properly trained for its main task, which is host defense. For example, in our laboratory, we infected two completely different pre-diabetic type 1 diabetes mouse models, the NOD and the RIP-LCMV,[36] with Coxsackie B3. This virus has been shown to systemically infect mice and has been epidemiologically associated with human type 1 diabetes. The Cox B infection usually lasts 10 days and involves the pancreas, but rarely the islets. Interestingly, acceleration of diabetes is only seen in some instances and depends on the timing of infection,[40-43] for example, when Coxsackie B3 is given to 10-week-old NOD mice or RIP mice 7 days post triggering of the diabetogenic response. Interestingly, it is important to note that an equally common outcome for viral infection is the lowering of diabetes penetrance. I would now like to discuss some impressive data supporting one of the underlying mechanisms for viral prevention of type 1 diabetes and then discuss some of the other potential mechanisms in a brief overview.

In recent unpublished observations, we discovered that infection of NOD mice could lead to invigoration of Tregs. Instead of enhancing immune function and exerting effector functions such as killing of infected cells or inducing interferon production,[44-47] Tregs can turn immune responses off. They do this through a variety of mechanisms in vivo, many of which involve the secretion of immune modulatory cytokines such as interleukin (IL)-10, IL-4, or transforming growth factor (TGF)-β. In our study, NOD mice that usually develop spontaneous autoimmune-mediated diabetes were infected with LCMV, which is cleared after 7 to 10 days. We observed a significant decrease in the incidence of type 1 diabetes, down from about 75% to about 15%. Tregs were subsequently isolated from these NOD mice several weeks after the protective viral infection and transferred into nonmanipulated naive NOD recipient mice during the pre-diabetic phase. Only the sorted Tregs from mice that had undergone the viral infection were potent enough to protect recipient NOD mice from development of diabetes. We conclude that the systemic viral infection invigorated the Tregs.

To understand the mechanism of protection, fluorescence-activated cell sorting analysis of Tregs from mice that had received the LCMV virus was compared with that of Tregs from nonmanipulated mice. The mice that had been infected produced a 10-fold increase in TGF-β. We then investigated whether in vitro suppression by virally invigorated Tregs was dependent on TGF-β by using cytokine blocking antibodies. Indeed, their suppressive function was decreased in the absence of TGF-β by about 50%. Next TGF-β was transfected into NOD-derived naive Tregs in vivo. Interestingly, the transfected Treg function was enhanced to the same level as the suppressive capacity seen in virally invigorated Tregs. We therefore conclude, from these findings, that viral infections enhance Treg activity in part by augmenting TGF-β production. Recent findings from our lab have demonstrated that this occurs in a Toll receptor-2-dependent fashion (C. Filippi and M.v.H., unpublished observations).

To summarize what we have learned so far regarding the mechanism by which viral infections can inhibit a diabetogenic response, please see Figure 2. TGF-β augmentation of Tregs is not solely responsible for virally mediated prevention of type 1 diabetes. It turns out that there are important general mechanisms that occur simultaneously, while the virus infection is ongoing. Based on our findings, these are associated with the viral induction of PD-1L and tumor necrosis factor (TNF)-α.[31] Both molecules have been shown to downmodulate immune responses and are important for the attrition of the antiviral immune response, when the viral infection is being cleared (with the purpose to limit excess immunopathology). Indeed, what happens after a viral infection, and this mechanism holds true for Coxsackie B viruses and other systemic infections, is that not only are the antiviral T-cells being eliminated, but PD-1L and TNF-α are mediating the bystander death of autoaggressive T-cells. This aspect of the mechanism results in a delay in the progression to type 1 diabetes but not a reduction in the overall incidence. The invigoration/activation of Treg cells is ultimately responsible for the observed reduction in incidence of type 1 diabetes in our model systems. Combined, these cytokine effects result in reduced incidence and delay of type 1 diabetes. These findings also illustrate rather elegantly that there are two components needed to prevent or cure type 1 diabetes therapeutically: 1) elimination of autoaggressive T-cells and 2) augmentation of Tregs to achieve long-term tolerance.

Conclusions and mechanistic hypothesis: How viral infections can stop type 1 diabetes. TGF-β augmentation of Tregs is not solely responsible for virally mediated prevention of type 1 diabetes. The viral induction of both PD-1L and TNF-α has been shown to downmodulate immune responses and are important for the attrition of the antiviral immune response, when the viral infection is being cleared. PD-1L and TNF-α also mediate the bystander death of autoaggressive T-cells.


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