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

Urszula Cytlak, Anastasia Resteu, Delfien Bogaert, Hye Sun Kuehn, Thomas Altmann, Andrew Gennery, Graham Jackson, Attila Kumanovics, Karl V. Voelkerding, Seraina Prader, Melissa Dullaers, Janine Reichenbach, Harry Hill, Filomeen Haerynck, Sergio D. Rosenzweig, Matthew Collin and Venetia Bigley ()
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Urszula Cytlak: Newcastle University
Anastasia Resteu: Newcastle University
Delfien Bogaert: Ghent University Hospital
Hye Sun Kuehn: National Institutes of Health
Thomas Altmann: Newcastle University
Andrew Gennery: Newcastle University
Graham Jackson: Newcastle upon Tyne Hospitals NHS Foundation Trust
Attila Kumanovics: University of Utah
Karl V. Voelkerding: University of Utah
Seraina Prader: University Children’s Hospital Zurich
Melissa Dullaers: Ghent University Hospital
Janine Reichenbach: University Children’s Hospital Zurich
Harry Hill: University of Utah
Filomeen Haerynck: Ghent University Hospital
Sergio D. Rosenzweig: National Institutes of Health
Matthew Collin: Newcastle University
Venetia Bigley: Newcastle University

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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-α, 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.

Date: 2018
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DOI: 10.1038/s41467-018-02977-8

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