The significant rise in T1D incidence in recent times cannot be explained by genetics alone and is likely due to the combination of genetic susceptibility loci interacting with non-genetic factors to impact immunity. Such findings suggest the environment either skews immune responses towards, or away from, autoimmunity. Indeed, several studies support a strong role for the environment (e.g. viruses) interacting with T1D susceptibility genes to promote innate immune activation and autoimmunity. Key components in the response to environmental triggers are Type 1 Interferons (IFNab), which stimulate DC maturation, TH1 responses, antibody production, and CTL activity. Knowledge providing molecular and genetic linkages has implicated IFNab as mediators of T1D. Allelism in two key IFNab signaling mediators, TYK2 and IFIH1, has been associated with T1D. Further, insulitic infiltrates of T1D patients reveal IFNab. Surprisingly, very little if any data exist that describes the effects of IFNab on human b cells.
Our overall goal is to understand the molecular interface between immune effectors and β cells in the context of T1D progression. Analyzing sections obtained from nPOD using immunohistochemistry and gene expression arrays we have observed that insulin positive cells in both T1D and autoantibody positive cases exhibit a Type 1 Interferon signaling signature. These data demonstrate that during T1D progression, IFNab are impacting b cells. Here we sought to determine the responses of b cells to IFNab, either alone or in combination with proinflammatory mediators.
Both Type 1 IFNs negatively impacted glucose- but not KCl-stimulated insulin secretion. This loss of function correlated with a decrease in glucose transporters. Treatment of human b cells with IFNa or IFNb alone did not modulate cell survival, but does significantly induce cell surface Class I HLA expression. FAS was specifically upregulated by IFNb and was not induced by IFNa. Accordingly, b cells exposed to a FAS agonistic antibody (aFAS) + IFNb were killed, while IFNa + aFAS did not reduce b cell viability. Cell Mediated Lymphocytotoxicity (CTL) assays were used to assess the effects of the observed immunological priming using Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) reactive CD8+ human T cell. Priming of b cells through pre-treatment with either IFNa or IFNb resulted in a significant increase in lysis of b cells. As expected, blocking FAS after IFNa priming had no impact on CTL lysis of b cells.
In conclusion, IFNa/b, which are important in the pathogenesis of T1D, promote beta cell dysfunction and prime bcells for immune surveillance and killing, albeit differentially. Even though IFNabuse the same receptor the signaling pathways are not identical. These novel and clinically relevant data further our understanding of the molecular interface between human immune effectors and human b cells.