In Autoimmune Diabetes the Transition from Benign to Pernicious Insulitis Requires an Islet Cell Response to Tumor Necrosis Factor α

Abstract

The islet-infiltrating and disease-causing leukocytes that are a hallmark of insulin-dependent diabetes mellitus produce and respond to a set of cytokine molecules. Of these, interleukin 1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ are perhaps the most important. However, as pleiotropic molecules, they can impact the path leading to β cell apoptosis and diabetes at multiple points. To understand how these cytokines influence both the formative and effector phases of insulitis, it is critical to determine their effects on the assorted cell types comprising the lesion: the effector T cells, antigen-presenting cells, vascular endothelium, and target islet tissue. Here, we report using nonobese diabetic chimeric mice harboring islets deficient in specific cytokine receptors or cytokine-induced effector molecules to assess how these compartmentalized loss-of-function mutations alter the events leading to diabetes. We found that islets deficient in Fas, IFN-γ receptor, or inducible nitric oxide synthase had normal diabetes development; however, the specific lack of TNF- α receptor 1 (p55) afforded islets a profound protection from disease by altering the ability of islet-reactive, CD4+ T cells to establish insulitis and subsequently destroy islet β cells. These results argue that islet cells play a TNF-α–dependent role in their own demise.

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

“…However, the in vivo role of the cytokine in diabetes development has not yet been fully elucidated. Its diabetogenic role was suggested in some studies (13)(14)(15)(16)(17)(18), whereas opposite effects were reported in other studies (19,20). Our IFN-␥/TNF-␣ synergism model nicely explains why transgenic expression of TNF-␣ alone could not induce diabetes in some of the previous studies in which pancreatic expression of TNF-␣ alone did not accelerate diabetes development (21).…”

“…The role of TNF-␣ as an effector has been extremely ambiguous. Its diabetogenic role was suggested in some studies (13)(14)(15)(16)(17)(18), whereas opposite effects were reported in other studies (19,20). Neonatal islet-specific expression of TNF-␣ promoted diabetes by enhancing the presentation of islet Ags (16,17).…”

“…Thus, it appears that TNF-␣ either inhibits or promotes diabetes depending on the condition under which it acts. The effect of IL-1 or NO on islet cell death was studied mostly in vitro (23,24), and their in vivo effects were not demonstrated (14,19). IFN-␥ has been regarded as a sensitizing or immunomodulatory cytokine rather than an effector molecule (25).…”

In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

“…Our evidence presented in this report supports the action of macrophage-mediated islet ␤-cell death because of several reasons: electron micrographs of islet infiltrates demonstrated the presence of macrophages adjoining dying ␤ cells, and importantly, islets from mice deficient in inducible nitricoxide synthase were efficiently destroyed by BDC T cells. 15 Moreover, NOD mice that harbor a mutation in the inducible nitric-oxide synthase gene developed diabetes with the same kinetics and penetrance as wild-type NOD mice (personal communication with John Mudgett, Merck Inc., San Diego, CA). Further, cytotoxicity assays as shown in Figure 8 (and by others 44 -46 ) needed the presence of macrophages.…”

“…It is important to note that in our model a role for Fas/FasL in mediating ␤-cell death is minor because Fas-deficient islets are efficiently destroyed by activated BDC T cells. 15 Finally, are activated macrophages also a participant in the natural disease? Certainly activated macrophages are a component of the infiltrate at the aggressive phase of the disease, that is, at the time of diabetes development.…”