The Transcription Factor Promyelocytic Leukemia Zinc Finger Protein Is Associated With Expression of Liver-Homing Receptors on Human Blood CD56(bright) Natural Killer Cells

The transcription factor promyelocytic leukemia zinc finger protein (PLZF) is involved in the development of natural killer (NK) cells and innate lymphoid cells, including liver-resident NK cells in mice. In human NK cells, the role of PLZF in liver residency is still unknown. Expression of PLZF in matched human peripheral blood- and liver-derived NK cells and the association of PLZF expression with surface molecules and transcription factors relevant for tissue residency were investigated using multiparameter flow cytometry and assessing single-cell messenger RNA (mRNA) levels. Intrahepatic cluster of differentiation (CD)56(bright) NK cells expressed significantly higher levels of PLZF than peripheral blood CD56(bright) NK cells, which were predominantly PLZF(lo). Expression of PLZF was highest within C-X-C motif chemokine receptor 6 (CXCR6)(+)CD69(+) liver-resident NK cells among intrahepatic CD56(bright) NK cell populations. Association of PLZF with liver-residency markers was also reflected at mRNA levels. A small PLZF(hi)CD56(bright) NK cell population was identified in peripheral blood that also expressed the liver-residency markers CXCR6 and CD69 and shared functional characteristics with liver-resident NK cells. Conclusion: PLZF is implicated as part of a transcriptional network that promotes liver residency of human NK cells. Expression of liver-homing markers on peripheral blood PLZF(hi)CD56(bright) NK cells identifies an intermediate population potentially contributing to the maintenance of liver-resident NK cells.