Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1

Interferon regulatory factor-1 (IRF-1), a transcriptional factor, regulates type I interferon and interferon-induced genes. It was reported that IRF-1 regulates important molecules required for inflammation and immune reactions. To investigate the role of IRF-1 in the development of autoimmune diabetes, we established IRF-1 deficient (IRF-1^-/- non-obese diabetic (NOD) mice. IRF-1-deficient C57BL/6J mice were out-crossed to NOD mice, and F1 were backcrossed to NOD mice. At the N8 generation, the heterozygote for IRF-1 mutation was intercrossed and N8F1 was obtained. Out of three NOD genotypes, IRF-1^+/+ and IRF-1^+/- developed spontaneous diabetes with an incidence of 47% (9/19) and 50% (10/20) by 30 weeks of age, respectively; whereas IRF-1^-/- did not develop diabetes (0/18, P<0.01 vs. ^+/+ and ^+/-). Histologically, IRF-1^+/+ and IRF-1^+/- had various degrees of insulitis, but IRF-1^-/- had no insulitis. In comparison with IRF-1^+/+, the percentage of CD4⁺ and Mac-1⁺ splenic cells significantly increased, whereas CD3⁺, CD8⁺ and B220⁺ cells decreased in IRF-1^-/-. Furthermore, spleen cell proliferation in response to Con A or murine GAD65 peptide, a major autoantigen of the pancreatic β-cell, significantly increased, and the IFN-γ/IL-10 ratio in the culture supernatant significantly decreased in IRF-1^-/-, suggesting Th2 deviation in cytokine balance. These results indicate that IRF-1 plays a key role in developing insulitis and diabetes in NOD mice.