Requirement for PBX1 in developmental programming of natural killer cells

Abstract

Abstract Maintenance of the optimally functional natural killer (NK) cells pool is essential for the host immune surveillance. Some intracellular growth-promoting factors (GPFs) have been reported as a vital new molecular component for maintenance homeostatic expansion of NK cells, but transcriptional regulation mechanism of Gpfs genes in NK cells is unclear. To better understand the underlying mechanism for NK cells be regulated to express GPFs as a secreted or intracellular isoform, we investigated the potential role of transcription factor PBX1 within the NK cell compartment by using Pbx1 gene-targeted mice. In terms of NK cell late development and homeostatic proliferation, here we report that PBX1 is the key transcriptional factor that underpins both of these events. The transcriptional factor PBX1 and GPFs are expressed in NK cell precursors and immature NK cells. After Pbx1 is knocked down on NK cells, NK cells shown a serious decline in the ability of expressing these GPFs. PBX1 regulates the transcription of GPFs genes in NK cells via direct binding. In the NK cell development, knocked down or excision of Pbx1 in mice harbor reduction of NK cells and the Pbx1-deficient developmental phenotype is NK cell intrinsic. In the NK cell homeostasis, PBX1 is necessary to support NK cell homeostasis in BM or spleen niche. The Pbx1-deficient mice is accompanied by impaired transition of NK cells from immature to mature, and diminished ability to differentiate into memory-like NK cells due to the impairment of GPFs. Our study indicates that PBX1 represent a novel regulatory element for supporting the homeostatic developmental program of NK cells, and provides the basis for improved approaches to immunotherapy for virus clearance and tumor surveillance.