IL-1α, IL-1β, and IFN-γ mark β cells for Fas-dependent destruction by diabetogenic CD4+ T lymphocytes
Abdelaziz Amrani, … , Sonny Bou, Pere Santamaria
Abdelaziz Amrani, … , Sonny Bou, Pere Santamaria
Published February 15, 2000
Citation Information: J Clin Invest. 2000;105(4):459-468. https://doi.org/10.1172/JCI8185.
View: Text | PDF
Article

IL-1α, IL-1β, and IFN-γ mark β cells for Fas-dependent destruction by diabetogenic CD4+ T lymphocytes

Abstract

Cytokines such as IL-1α, IL-1β, and IFN-γ have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4+ T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, β cell–specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1α–, IL-1β–, and IFN-γ–treated β cells from NOD mice. Untreated NOD β cells and cytokine-treated β cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR–transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4+ T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect β cell–specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1α, IL-1β, and IFN-γ in autoimmune diabetes, whereby these cytokines mark β cells for Fas-dependent lysis by autoreactive CD4+ T cells.

Authors

Abdelaziz Amrani, Joan Verdaguer, Shari Thiessen, Sonny Bou, Pere Santamaria

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Cytotoxic activity of 4.1-CD4+ CTL. (a) PMA and ionomycin–treated and un...
Cytotoxic activity of 4.1-CD4+ CTL. (a) PMA and ionomycin–treated and untreated 4.1-CD4+ T cells, propagated from pancreatic islets of acutely diabetic 4.1-NOD mice, were tested for cytotoxic activity against NOD and B6 islet cells (i.c.) (left) and L1210-Fas+ and L1210-Fas– fibroblasts (right). (b) Cytotoxic activity of serine esterase–positive 4.1-CD4+ CTL and 8.3-CD8+ CTL clones against NOD and B6 islet cells at a 1:5 target-to-effector (T:E) ratio. (c) Cytolytic activity of a representative 4.1-CD4+ CTL clone against L1210-Fas+ and L1210-Fas– cells at a 1:5 T:E ratio. (d) and (e) Cytolytic activity of in vitro–differentiated 4.1-CD4+ CTL against NOD (d) or NOD.lpr+/+ (e) islet cells cultured overnight in the absence (0) or presence of IFN-γ (250 U/mL) or IL-1α (100 U/mL) at a 1:10 T:E ratio. Although overnight IL-1α treatment caused a significant reduction in islet yield, the spontaneous chromium release by the surviving islet cells was similar to that by untreated or IFN-γ–treated islet cells (< 35%). (f) Cytolytic activity of 4.1-CD4+ CTL against cytokine-treated NOD islet cells (250 U/mL IFN-γ, 100 U/mL IL-1α, or 250 U/mL IFN-γ + 10 U/mL IL-1α) in the presence of blocking concentrations of anti–MHC class II and class I mAbs (at a 1:10 T:E ratio). (g) Cytolytic activity of 4.1-CD4+ CTL against IFN-γ–(250 U/mL) and IL-1α–treated (10 U/mL) NOD islet cells in the presence of a caspase inhibitor (CI) or a control inhibitor (granzyme B inhibitor; GBI). (h) Cytolytic activity of 4.1-CD4+ CTL against cytokine-treated NOD islet cells (250 U/mL IFN-γ, 100 U/mL IL-1α, 100 U/mL IL-1β, or 250 U/mL IFN-γ + 10 U/mL IL-1α or IL-1β). The figures are representative of 2–3 different experiments (mean ± SEM). Iono, ionomycin.