Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha.
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 alpha production, relative to IFN-beta+/+ mice. Notably, constitutive and induced expression of tumor necrosis factor alpha 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-1-, 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, granulocyte-macrophage. 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.
Toronto General Research Institute, University Health Network, Toronto, ON, Canada MG5 2M1.
Raj
R
Deonarain
Amit
A
Verma
Andrew C G
AC
Porter
Dirk R
DR
Gewert
Leonidas C
LC
Platanias
Eleanor N
EN
Fish
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D002455:Cell Division; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D016130:Immunophenotyping; D016899:Interferon-beta / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D038042:Myelopoiesis / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015704:CD4 Antigens; D016827:CD8 Antigens; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor