Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment

Abstract

A detailed understanding of the molecular pathways and cellular interactions that result in islet beta cell (β cell) destruction is essential for the development and implementation of effective therapies for prevention or reversal of type 1 diabetes (T1D). However, events that define the pathogenesis of human T1D have remained elusive. This gap in our knowledge results from the complex interaction between genetics, the immune system, and environmental factors that precipitate T1D in humans. A link between genetics, the immune system, and environmental factors are type 1 interferons (T1-IFNs). These cytokines are well known for inducing antiviral factors that limit infection by regulating innate and adaptive immune responses. Further, several T1D genetic risk loci are within genes that link innate and adaptive immune cell responses to T1-IFN. An additional clue that links T1-IFN to T1D is that these cytokines are a known constituent of the autoinflammatory milieu within the pancreas of patients with T1D. The presence of IFNα/β is correlated with characteristic MHC class I (MHC-I) hyperexpression found in the islets of patients with T1D, suggesting that T1-IFNs modulate the cross-talk between autoreactive cytotoxic CD8⁺ T lymphocytes and insulin-producing pancreatic β cells. Here, we review the evidence supporting the diabetogenic potential of T1-IFN in the islet microenvironment.

Keywords: CD8+ T cell; beta cells; humans; type 1 diabetes; type 1 interferons.

Figure 1

CD8 T cells are the major leukocyte component of the insulitis lesion in type 1 diabetes (T1D) as well as recurrent disease. Pancreatic sections [courtesy of Network for Pancreatic Organ Donors with Diabetes (nPOD)] were examine histologically for the presence of islet invading immune cells. (A) Section taken from a pancreas organ donor with T1D (nPOD case 6052). The tissue section was immunofluorescently stained for glucagon (yellow) to identify the islet, CD4 T lymphocytes (red), and CD8 T lymphocytes (green). Within this islet cytotoxic CD8⁺ T lymphocytes (CTLs) are the predominant T cell type observed. Image courtesy of Martha Campbell-Thompson, DVM/PhD (University of Florida). (B) Section taken from a pancreas transplant biopsy, from an simultaneous pancreas and kidney (SPK) recipient who had developed recurrence of T1D. Tissues were stained for insulin (red), CD4 T lymphocytes (blue), and CD8 T lymphocytes (teal). Within the insulitic lesions, CTLs represented the dominant T cell found. Figure shows islets with both CD8 than CD4 T cells, but most islets were primarily infiltrated by CD8 T cells. Green/yellow bright stains represent non-specific fluorescence from red blood cells. Image courtesy of Alberto Pugliese, MD, Francesco Vendrame, MD, and George Burke, III, MD, University of Miami.

Figure 2

Type 1 interferons (T1-IFNs) are a catastrophic feature of the islet microenvironment in type 1 diabetes (T1D). Based on previous literature and current findings, T1-IFNs are consistently found in the islet autoinflammatory milieu and represent a viable signal that may precipitate diabetogenicity in T1D. With respect to β cells, these cytokines can impair insulin secretory function, possibly through the induction of endoplasmic reticulum (ER) stress as well as by impairing mitochondrial bioenergetics. Whole transcriptome analysis reveals decreased expression of genes involved in the regulation of ATP production and transport, including ATP5A (1), SLC25A3 (2), and SLC25A5/6 (3). Reduction in these transcripts likely lead to decreases in the cytosolic ATP/ADP ratio (4) that is required for glucose-stimulated insulin secretion by β cells (5). T1-IFNs also enhance the autoimmune surveillance of pancreatic β cells through induction of the immunoproteasome (6), de novo synthesis of MHC class I and genes responsible for the peptide loading complex (7 and 8), as well as enhanced surface expression of MHC class I (9). This increased capacity for antigen presentation results in a functional ability of cytotoxic CD8⁺ T lymphocyte (CTL)-mediated β cell destruction, which is further augmented by the ability of T1-IFN to amplify infiltrating CTL cytotoxic capacity through STAT4-induced granzyme B production (10 and 11).