The early colocalization of T cells and the potent immunostimulatory cytokine IFN-␥ to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-␥ in this process. First, the presence of CD4 ϩ and CD8 ϩ cells, which secrete lesional IFN-␥ , was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-␥ receptor (IFN ␥ R) 0 mice to generate apoE 0/IFN ␥ R 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-␥ promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-␥ signaling may lead to the formation of more lipid-poor and stable atheromata. ( J. Clin. Invest. 1997. 99:2752-2761.)

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