The Transcription Factor ZNF683/HOBIT Regulates Human NK-Cell Development

• Main Authors: Mirte Post, Angelica Cuapio, Markus Osl, Dorit Lehmann, Ulrike Resch, David M. Davies, Martin Bilban, Bernhard Schlechta, Wolfgang Eppel, Amit Nathwani, Dagmar Stoiber, Jan Spanholtz, Emilio Casanova, Erhard Hofer
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-05-01
• Series: Frontiers in Immunology
• Subjects: ZNF683/HOBIT; natural killer cells; CD56; ex vivo differentiation; NK-cell development
• Online Access: http://journal.frontiersin.org/article/10.3389/fimmu.2017.00535/full

We identified ZNF683/HOBIT as the most highly upregulated transcription factor gene during ex vivo differentiation of human CD34+ cord blood progenitor cells to CD56+ natural killer (NK) cells. ZNF683/HOBIT mRNA was preferentially expressed in NK cells compared to other human peripheral blood lymphocytes and monocytes. During ex vivo differentiation, ZNF683/HOBIT mRNA started to increase shortly after addition of IL-15 and further accumulated in parallel to the generation of CD56+ NK cells. shRNA-mediated knockdown of ZNF683/HOBIT resulted in a substantial reduction of CD56−CD14− NK-cell progenitors and the following generation of CD56+ NK cells was largely abrogated. The few CD56+ NK cells, which escaped the developmental inhibition in the ZNF683/HOBIT knockdown cultures, displayed normal levels of NKG2A and KIR receptors. Functional analyses of these cells showed no differences in degranulation capacity from control cultures. However, the proportion of IFN-γ-producing cells appeared to be increased upon ZNF683/HOBIT knockdown. These results indicate a key role of ZNF683/HOBIT for the differentiation of the human NK-cell lineage and further suggest a potential negative control on IFN-γ production in more mature human NK cells.