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, Venetia Bigley

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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.

Original languageEnglish
Article number1239
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 27 Mar 2018

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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