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

Abstract

We identified <i>ZNF683/HOBIT</i> as the most highly upregulated transcription factor gene during <i>ex vivo</i> 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 <i>ex vivo</i> 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.