Interferon-γ Impacts at Multiple Points during the Progression of Autoimmune Diabetes

The role of Interferon-γ in autoimmune diabetes was assessed by breeding a null mutation of the Interferon-γ receptor α chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the Interferon-γ gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis--both the kinetics and penetrance--and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet β cell targets.