Interferons in antiviral defense and autoimmunity : focus on type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a disease characterized by the loss of insulin producing beta-cells in the pancreatic islets of Langerhans. Interferons (IFNs), produced by immune cells and infected parenchymal cells, may be protective or damaging in the pathogenesis of T1D. An intact beta-cell response to IFNs is critical for beta-cell survival and protection from diabetes during a Coxsackievirus B (CVB) infection, a virus associated with T1D in humans. It has also been suggested that IFNs may protect from natural killer (NK) cell dependent destruction. Importantly, while being protective during infection with CVB, the pancreatic beta-cell response to cytokines is crucial for the development of type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse. NOD mice overexpressing the Suppressor of Cytokine Signaling 1 (SOCS-1) specifically in the beta-cells are protected from spontaneous diabetes. The work in this thesis focuses on the mechanisms behind the protective and damaging effects of IFNs in the pathogenesis of T1D. Moreover, it identifies a possible source of IFNgamma during CVB infection.

This thesis shows that IFNs trigger an antiviral state in mouse and human islets. Both the RNase L and the dsRNA-dependent protein kinase (PKR) pathways are induced by IFNs in mouse islets and play important roles in providing unique and complementary antiviral activities that regulate the outcome of CVB infection. Moreover, this thesis shows that human islet cells also respond to IFNs by expressing signature genes of antiviral defense. It further demonstrates that human islets express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which contribute to the production of type I IFN in infected cells. These observations suggest that human islet cells have the possibility to detect an invading virus and to produce type I IFNs during an infection. The work presented in this thesis identifies the NK cell as a possible contributor of IFNgamma during CVB infection: it shows that CVB interferes with the expression of NK cell receptor ligands on infected cells and that IFNgamma production, rather than cytotoxicity, marks the early human NK cell response to CVB infection. Finally, this thesis gives new insights into how IFNs, by acting directly on beta-cells, contribute to disease development in the NOD mouse. It demonstrates that the beta-cell, by responding to thepro-inflammatory pancreas milieu, strongly influences the percentage of self-reactive CD8 T-cells in the pancreas.

In conclusion, this thesis supports the notion that cytokine-exposed islet cells affect islet infection and inflammation, highlighting an important role for the beta-cell in the local regulation of the diabetogenic process. By providing a basic understanding for how beta-cells respond to IFNs, and how this relates to their defense against CVB and to the accumulation of pathogenic cells in the pancreas, it may contribute to a future unraveling of the mechanisms underlying beta-cell loss in T1D.