Protection against type 1 diabetes upon Coxsackievirus B4 infection and iNKT cell stimulation : role of suppressive macrophages

Abstract : INKT cells are non-conventional T lymphocytes that are restricted to glycolipid presenting CD1d molecule. iNKT cells express an invariant TCR a chain (Va14-Ja18 in mice and Va28-Ja18 in humans). Their particularity is to rapidly produce copious amounts of cytokines (IFN-? and IL-4) after activation and to activate other cells of the immune system such as dendritic cells, NK cells and T lymphocytes. iNKT cells, therefore, form a bridge between innate and adaptive immune responses. Type 1 diabetes is an autoimmune disease characterized by the destruction of pancreatic ß cells whose role is to produce insulin. While diabetes development can clearly be associated with genetic polymorphisms, environmental factors were also implicated in the etiology of the disease. Numerous studies suggest that viral infections, particularly infections with Coxsackievirus B4 (CVB4), could be implicated in the development of type 1 diabetes. Our study was performed with NOD mice that develop type 1 diabetes around 15 weeks of age and with proinsulin 2 knockout NOD mice (Pro-ins2-/-) which become diabetic around 8 weeks of age. Our results show that CVB4 infection induces accelerated diabetes in around half of NOD and Pro-ins2-/- mice compared to uninfected mice. However, the activation of iNKT cells with their agonist, aGalactosylceramide (aGalCer), at the time of infection greatly decreases diabetes incidence. CVB4 infection induces a strong recruitment of macrophages into the pancreas. Interestingly, iNKT cell activation modifies the function of these macrophages. Indeed, pancreatic macrophages of CVB4 infected mice strongly express IL-1, IL-6 and TNF-a, indicating their pro-inflammatory character. On the contrary, macrophages of mice infected with CVB4 and treated with aGalCer express low levels of these cytokines, but strong levels of suppressive enzymes iNOS (inducible NO synthase), IDO (Indoleamine 2,3-dioxygenase) and arginase I. The use of inhibitors of these enzymes showed that diabetes prevention is induced by IDO. We have also observed that autoreactive T cells strongly infiltrate the pancreatic islets after CVB4 infection. It is interesting to note that the high diabetes incidence of CVB4 infected mice is associated with an increased frequency of IFN-? producing autoreactive T cells in pancreatic islets. On the contrary, the frequency of these cells is very low in infected mice treated with aGalCer. The inhibition of IFN-? production is dependent on IDO enzyme, since the use of its inhibitor strongly increases IFN-? production by anti-islet T cells and diabetes incidence. To summarize, our results show that iNKT cell activation during the infection with CVB4 induces immunosuppressive macrophages in the pancreas. These cells inhibit the function of autoreactive T cells and prevent diabetes development.
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Liana Ghazarian. Protection against type 1 diabetes upon Coxsackievirus B4 infection and iNKT cell stimulation : role of suppressive macrophages. Immunology. Université René Descartes - Paris V, 2013. English. ⟨NNT : 2013PA05T097⟩. ⟨tel-01071267⟩

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