Hlx homeobox transcription factor negatively regulates interferon-γ production in monokine-activated natural killer cells

Brian Becknell, Tiffany L. Hughes, Aharon G. Freud, Bradley W. Blaser, Jianhua Yu, Rossana Trotta, Hsiaoyin C. Mao, Marie L. Caligiuri de Jesús, Mohamad Alghothani, Don M. Benson, Amy Lehman, David Jarjoura, Danilo Perrotti, Michael D. Bates, Michael A. Caligiuri

Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-gamma). Although there is some knowledge about molecular mechanisms that induce IFN-gamma in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-gamma production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-gamma. Ectopic Hlx expression decreases IFN-gamma synthesis in primary human NK cells and IFN-gamma promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-gamma transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-gamma, in part through the targeted depletion of STAT4.