Negative regulation of IFN-alpha/beta signaling by IFN regulatory factor 2 for homeostatic development of dendritic cells.
The development and cooperation of distinct subsets of antigen-presenting cells, particularly dendritic cells (DCs), may be critical for maintaining homeostatic immune responses. Recently, much attention has been focused on IFN-alpha/beta, the cytokines induced en masse by virus infection or the activation of Toll-like receptors, in the context of DC activation. Here, we show that mice deficient in IFN regulatory factor 2 exhibit selective loss of CD8alpha- DCs, the so-called myeloid DCs, which is accompanied by a notable increase in CD11c-CD11bhigh other myeloid lineage cells. Such deficiency is intrinsic to the bone marrow precursors, in which the abnormal induction of IFN-alpha/beta genes causes excessive IFN signaling. The critical function of IFN regulatory factor 2 in the negative regulation of IFN-alpha/beta signaling is underscored by the observation that the deficiency is rescued by introducing an additional null mutation for the IFN receptor complex. In view of accumulating evidence of the critical role of IFN-alpha/beta signaling in DC activation, our present study offers a unique example in that the magnitude of a cytokine signal should be properly balanced in a stage-specific manner during the differentiation and activation of DCs.
Department of Immunology, Faculty of Medicine and Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Kenya
K
Honda
Tatsuaki
T
Mizutani
Tadatsugu
T
Taniguchi
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006706:Homeostasis; D007150:Immunohistochemistry; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins; D012475:Salmonella; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D050836:Interferon Regulatory Factor-2; D016898:Interferon-alpha; C494230:Irf2 protein, mouse; D008070:Lipopolysaccharides; D012097:Repressor Proteins; D014157:Transcription Factors; D016899:Interferon-beta