Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

被引：59

作者：

Cytlak, Urszula ^{[1
]}

Resteu, Anastasia ^{[1
]}

Bogaert, Delfien ^{[2
,3
,4
,5
,6
,7
]}

Kuehn, Hye Sun ^{[8
]}

Altmann, Thomas ^{[1
,9
]}

Gennery, Andrew ^{[1
,9
]}

Jackson, Graham ^{[9
,10
]}

Kumanovics, Attila ^{[11
]}

Voelkerding, Karl V. ^{[11
]}

Prader, Seraina ^{[12
]}

Dullaers, Melissa ^{[2
,5
,6
,13
]}

Reichenbach, Janine ^{[12
,14
,15
,16
]}

Hill, Harry ^{[11
,17
]}

Haerynck, Filomeen ^{[2
,3
,5
,6
]}

Rosenzweig, Sergio D. ^{[8
]}

Collin, Matthew ^{[9
]}

Bigley, Venetia ^{[1
,9
]}

机构：

[1] Newcastle Univ, Inst Cellular Med, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Ghent Univ Hosp, Dept Pulm Med, Primary Immunodeficiency Res Lab, C Heymanslaan 10, B-9000 Ghent, Belgium

[3] Ghent Univ Hosp, Div Paediat Immunol & Pulmonol, Dept Paediat, C Heymanslaan 10, B-9000 Ghent, Belgium

[4] Ghent Univ Hosp, Ctr Med Genet, C Heymanslaan 10, B-9000 Ghent, Belgium

[5] Ghent Univ Hosp, Ctr Primary Immunodeficiency Jeffrey Modell Diag, Heymanslaan 10, B-9000 Ghent, Belgium

[6] Ghent Univ Hosp, Res Ctr, Heymanslaan 10, B-9000 Ghent, Belgium

[7] VIB Inflammat Res Ctr, Lab Immunoregulat, Technol Pk 927, B-9052 Ghent, Belgium

[8] NIH, Clin Ctr, Dept Lab Med, 10 Ctr Drive MSC 1508, Bethesda, MD 20892 USA

[9] Newcastle Upon Tyne Hosp NHS Fdn Trust, Freeman Rd, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England

[10] Newcastle Univ, Northern Inst Canc Res, Paul Ogorman Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4AD, Tyne & Wear, England

[11] Univ Utah, Dept Pathol, 50 North Med Dr, Salt Lake City, UT 84132 USA

[12] Univ Childrens Hosp Zurich, Div Immunol, Steinwiesstr 75, CH-8032 Zurich, Switzerland

[13] Univ Ghent, Dept Internal Med, De Pintelaan 185, B-9000 Ghent, Belgium

[14] Univ Childrens Hosp Zurich, Childrens Res Ctr, Steinwiesstr 75, CH-8032 Zurich, Switzerland

[15] Univ Zurich, Inst Regenerat Med IREM Associated Grp, Wagistr 12, CH-8952 Zurich, Switzerland

[16] Univ Zurich, Competence Ctr Appl Biotechnol & Mol Med CABMM, Irchel Campus,Winterthurerstr 190, CH-8057 Zurich, Switzerland

[17] Univ Utah, Dept Paediat & Med, 50 North Med Dr, Salt Lake City, UT 84132 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金; 欧盟第七框架计划;

关键词：

MULTIPLE-MYELOMA CELLS; B-CELLS; DIFFERENTIATION; MUTATIONS; RESPONSES; MOUSE; IMMUNODEFICIENCY; DEFICIENCY; PROTEINS; SURVIVAL;

D O I：

10.1038/s41467-018-02977-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-alpha, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

引用

页数：10

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