Ikaros is required for plasmacytoid dendritic cell differentiation

被引:110
作者
Allman, David
Dalod, Marc
Asselin-Paturel, Carine
Delale, Thomas
Robbins, Scott H.
Trinchieri, Giorgio
Biron, Christine A.
Kastner, Philippe
Chan, Susan [1 ]
机构
[1] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[2] Univ Mediterranee, Ctr Immunol Marseille Luminy, Marseille, France
[3] INSERM, U631, Marseille, France
[4] CNRS, UMR 6102, Marseille, France
[5] Schering Plough Res Inst, Lab Immunol Res, Dardilly, France
[6] Brown Univ, Div Biol & Med, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA
[7] Univ Louis Pasteur Strasbourg 1, CU, Illkirch, CNRS,INSERM,Inst Genet & Biol Mol, Strasbourg, France
[8] Univ Louis Pasteur Strasbourg 1, CU, Illkirch, CNRS,INSERM,Inst Cellulaire, Strasbourg, France
关键词
INTERFERON-PRODUCING CELLS; INHIBITORY NK RECEPTOR; TRANSCRIPTION FACTOR; STRANDED-RNA; IFN-ALPHA; ACTIVATION; RESPONSES; RECOGNITION; GENERATION; INDUCTION;
D O I
10.1182/blood-2006-03-007757
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Plasmacytoid dendritic cells (pDCs) are specialized DCs that produce high levels of type I IFN upon viral infection. Despite their key immunoregulatory role, little is known about pDC ontogeny or how developmental events regulate their function. We show that mice expressing low levels of the transcription factor Ikaros (Ik(L/L)) lack peripheral pDCs, but not other DC subsets. Loss of pDCs is associated with an inability to produce type I IFN after challenge with Toll-like receptor-7 and -9 ligands, or murine cytomegalovirus (MCMV) infection. In contrast, conventional DCs are present in normal numbers and exhibit normal responses in vivo after challenge with MCMV or inactivated toxoplasma antigen. Interestingly, Ik(L/L) bone marrow (BM) cells contain a pDC population that appears blocked at the Ly-49Q(-) stage of differentiation and fails to terminally differentiate in response to Flt-3L, a cytokine required for pDC differentiation. This differentiation block is strictly dependent on a cell-intrinsic requirement for Ikaros in pDC-committed precursors. Global gene expression profiling of Ik(L/L) BM pDCs reveals an upregulation of genes not normally expressed, or expressed at low levels, in WT pDCs. These studies suggest that Ikaros controls pDC differentiation by silencing a large array of genes.
引用
收藏
页码:4025 / 4034
页数:10
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