title: IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells.
abstract: NK cell development is far less understood compared with that of T and B cells despite the critical importance of NK cells in innate immunity. Mice lacking the transcription factor IFN regulatory factor-2 (IRF-2) are known to exhibit NK cell deficiency. However, the role of IRF-2 in NK cell development has remained unclear. In this study we found that NK cell deficiency in the periphery in IRF-2-deficient mice was due to selective loss of mature NK cells, but not to maturation arrest, and NK cells in these mice exhibited very immature surface phenotypes (CD11b(low)Dx5(low)) with highly compromised NK receptor expression. In contrast, IRF-2-deficient NK cells in bone marrow (BM) showed relatively mature phenotypes (CD11b(low)Dx5(high)) with less compromised NK receptor repertoire. Furthermore, BM NK cells in IRF-2-deficient mice were found to proliferate almost normally, but underwent accelerated apoptosis. These observations indicated that NK cell maturation could advance up to a late, but not the final, stage in the BM, whereas these cells were incapable of contributing to the peripheral NK cell pool due to premature death in the absence of IRF-2. In contrast, NK cell numbers and Ly49 expression were much more severely reduced in BM in IL-15-deficient mice than in IRF-2(-/-) mice. The differential peripheral and central NK cell deficiencies in IRF-2(-/-) mice thus revealed a novel late checkpoint for NK cell maturation, distinct from the early IL-15-dependent expansion stage.
authors.affiliation: Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto, Japan. shin-t@sch.md.shinshu-u.ac.jp
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Taki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nakajima
authors.forename: Eri
authors.initials: E
authors.lastname: Ichikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Hida
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016130:Immunophenotyping; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D037181:Lectins, C-Type; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000096:biosynthesis; D055630:Receptors, NK Cell Lectin-Like; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D004268:DNA-Binding Proteins; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma