Defective development of splenic and epidermal CD4+ dendritic cells in mice deficient for IFN regulatory factor-2.
Dendritic cells (DCs) play important roles in the initiation and regulation of immune responses. Although several subsets of DCs were identified according to their expression of surface molecules such as CD4, CD8, and CD11b, the regulatory mechanism for the development and homeostasis of these DC subsets remains unclear. Here we show that mice lacking IFN regulatory factor-2 (IRF-2(-/-) mice) exhibited a marked and selective defect in splenic CD4(+)CD11b(+)DCs, instead of CD8 alpha(+)CD11b(-)DCs that were reported to be missing in mice lacking the related transcription factor IRF-8. Furthermore, the numbers of epidermal Langerhans cells in IRF-2(-/-) mice were reduced at least in part because of the lack of the CD4(+)CD11b(+) subset. Studies with radiation bone marrow chimeras as well as in vitro retrovirus-mediated gene transduction showed that IRF-2 was required cell-autonomously for the development of myeloid-related DCs. Notably, these abnormalities in DCs diminished in mice lacking both IRF-2 and the IFN-alpha/beta receptor, indicating that IRF-2 acted through negatively regulating IFN-alpha/beta signals. In contrast, natural killer cells still showed developmental arrest in these double mutant mice, indicating that the mode of action of IRF-2 for CD4(+)DC development is distinct from that for natural killer cell development. Our current findings thus pointed to a previously unknown unique cell-type-selective multimode function of IRF-2 in the regulation of lymphohematopoiesis.
Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan.
Eri
E
Ichikawa
Shigeaki
S
Hida
Yoshiki
Y
Omatsu
Susumu
S
Shimoyama
Kazuhiko
K
Takahara
Shinichi
S
Miyagawa
Kayo
K
Inaba
Shinsuke
S
Taki
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D050836:Interferon Regulatory Factor-2; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins; D013154:Spleen / Q000378:metabolism*; D014157:Transcription Factors
D039481:CD11b Antigen; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors