Critical roles for IFN-β in lymphoid development, myelopoiesis, and tumor development:: Links to tumor necrosis factor α

We have generated mice null for IFN-beta and report the diverse consequences of IFN-beta for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN-beta(-/-) mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor a production, relative to IFN-beta(+/+) mice. Notably, constitutive and induced expression of tumor necrosis factor a is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-beta(-/-) mice. We also observe an altered splenic architecture in IFN-beta(-/-) mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-beta(-/-) mice, associated with a decrease in B220(+ve/high)/CD43(-ve) BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-l-, and Gr-1-positive cells are also substantially decreased in IFN-beta(-/-) mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocytemacrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN-beta(-/-) background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-beta(-/-) mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-beta is required during different stages of maturation in the development of the immune system.