Critical roles for IFN in lymphoid development, myelopoiesis, and tumor development: Links to tumor necrosis factor (original) (raw)

2003, Proceedings of The National Academy of Sciences

We have generated mice null for IFN-␤ and report the diverse consequences of IFN-␤ 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-␤ ؊/؊ mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor ␣ production, relative to IFN-␤ ؉/؉ mice. Notably, constitutive and induced expression of tumor necrosis factor ␣ is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-␤ ؊/؊ mice. We also observe an altered splenic architecture in IFN-␤ ؊/؊ mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-␤ ؊/؊ 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-1-, and Gr-1-positive cells are also substantially decreased in IFN-␤ ؊/؊ 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-␤ ؊/؊ background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-␤ ؊/؊ mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-␤ is required during different stages of maturation in the development of the immune system.