The transcriptional repressor Gfi1 controls STAT3-dependent dendritic cell development and function

被引:98
作者
Rathinam, C
Geffers, R
Yücel, R
Buer, J
Welte, K
Möröy, T
Klein, C
机构
[1] Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany
[2] German Res Ctr Biotechnol, D-38124 Braunschweig, Germany
[3] Univ Klinikum Essen, Inst Zellbiol Tumorforsch, D-45122 Essen, Germany
关键词
D O I
10.1016/j.immuni.2005.04.007
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The mechanisms controlling the differentiation of dendritic cells (DCs) remain largely unknown. Using a transcriptional profiling approach, we identified Gfi1 as a novel critical transcription factor in DC differentiation. Gfi1(-/-) mice showed a global reduction of myeloid and lymphoid DCs in all lymphoid organs whereas epidermal Langerhans cells were enhanced in number. In vivo, Gfi1(-/-) DCs showed striking phenotypic and functional alterations such as defective maturation and increased cytokine production. In vitro, Gfi1(-/-) hematopoietic progenitor cells were unable to develop into DCs. Instead, they differentiated into macrophages, suggesting that Gfi1 is a critical modulator of DC versus macrophage development. Analysis of hematopoietic chimeras and retrovirus-reconstituted hematopoietic progenitor cells established a cell autonomous and nonredundant role for Gfi1 in DC development. The developmental defect of Gfi1(-/-) progenitor cells was associated with decreased STAT3 activation. In conclusion, we have identified Gfi1 as a critical transcription factor that controls DC versus macrophage development and dissociates DC maturation and activation.
引用
收藏
页码:717 / 728
页数:12
相关论文
共 51 条
[11]   Targeted transcriptional repression of Gfi1 by GFI1 and GFI1B in lymphoid cells [J].
Doan, LL ;
Porter, SD ;
Duan, Z ;
Flubacher, MM ;
Montoya, D ;
Tsichlis, PN ;
Horwitz, M ;
Gilks, CB ;
Grimes, HL .
NUCLEIC ACIDS RESEARCH, 2004, 32 (08) :2508-2519
[12]   Growth factor independence-1B expression leads to defects in T cell activation, IL-7 receptor α expression, and T cell lineage commitment [J].
Doan, LL ;
Kitay, MK ;
Yu, Q ;
Singer, A ;
Herblot, S ;
Hoang, T ;
Bear, SE ;
Morse, HC ;
Tsichlis, PN ;
Grimes, HL .
JOURNAL OF IMMUNOLOGY, 2003, 170 (05) :2356-2366
[13]   Targets of the transcriptional repressor oncoprotein Gfi-1 [J].
Duan, ZJ ;
Horwitz, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (10) :5932-5937
[14]   PROGRESSION OF INTERLEUKIN-2 (IL-2)-DEPENDENT RAT T-CELL LYMPHOMA LINES TO IL-2-INDEPENDENT GROWTH FOLLOWING ACTIVATION OF A GENE (GFI-1) ENCODING A NOVEL ZINC FINGER PROTEIN [J].
GILKS, CB ;
BEAR, SE ;
GRIMES, HL ;
TSICHLIS, PN .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (03) :1759-1768
[15]  
Grimes HL, 1996, MOL CELL BIOL, V16, P6263
[16]   PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells [J].
Guerriero, A ;
Langmuir, PB ;
Spain, LM ;
Scott, EW .
BLOOD, 2000, 95 (03) :879-885
[17]   Transcriptional profiling identifies Id2 function in dendritic cell development [J].
Hacker, C ;
Kirsch, RD ;
Ju, XS ;
Hieronymus, T ;
Gust, TC ;
Kuhl, C ;
Jorgas, T ;
Kurz, SM ;
Rose-John, S ;
Yokota, Y ;
Zenke, M .
NATURE IMMUNOLOGY, 2003, 4 (04) :380-386
[18]   Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells [J].
Hock, H ;
Hamblen, MJ ;
Rooke, HM ;
Schindler, JW ;
Saleque, S ;
Fujiwara, Y ;
Orkin, SH .
NATURE, 2004, 431 (7011) :1002-1007
[19]   Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation [J].
Hock, H ;
Hamblen, MJ ;
Rooke, HM ;
Traver, D ;
Bronson, RT ;
Cameron, S ;
Orkin, SH .
IMMUNITY, 2003, 18 (01) :109-120
[20]   Regulation of socs gene expression by the proto-oncoprotein GFI-1B -: Two routes for STAT5 target gene induction by erythropoietin [J].
Jegalian, AG ;
Wu, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (03) :2345-2352