IFN-a Evokes a Heterogeneous, Rapid ROS Response from a Subset of Human Islet Beta Cells in Situ

A large body of evidence reveals a web of complex, multifaceted genetic, and environmental factors that influences incidence of T1D. Among these, viral infection has been discussed as a factor implicated in onset. Production of type 1 interferons (IFN) is the archetypal immune response to viral infection. Indeed, at-risk children exhibit IFN-associated transcriptional profiles and IFN-stimulated genes are elevated in new onset T1D patients. IFN-α induces ER stress, substantial overexpression of HLA class 1, and insulitis in the islet. β-cells are known to be sensitive to reactive oxygen species (ROS) accumulation which may contribute to autoimmunogenicity in the IFN response. In order to detect the in vivo effects of IFN-α on the physiology of human islets, we conducted intravital microscopy studies of human islets transplanted in the mouse kidney - following transduction with a ratiometric fluorescent redox biosensor. These studies revealed that intravenous IFN-α elicited a mild overall accumulation of ROS in human islets, but rapid and pronounced accumulation of ROS in a subset of islet β-cells - a population of cells we termed, “ROSponders." Interestingly, the percentage of β-cells categorized as ROSponders was variable between donors (ranging from ~1% to 6% of all β-cells). Recent observations have drawn attention to the importance of β-cell expression and functional heterogeneity within the islet. Furthermore, recent work suggests that blockade of IFN-α signaling prior to clinical T1D manifestation may intercept autoimmunity and abort onset. Altogether, this work identifies novel heterogeneity of response to an inflammatory cytokine implicated in T1D onset and may inform future approaches to the treatment of T1D. Disclosure M. Arvin: None. C. Muralidharan: None. A. M. Conteh: None. M. M. Martinez irizarry: None. K. Orr: None. K. W. Dunn: None. A. K. Linnemann: None. Funding Human Islet Research Network (RRID:SCR_014393; UC4 DK104162); National Institutes of Health (3T32DK064466-18S1)