Intrahepatic development of liver-resident natural killer cells (LYM2P.739)

Abstract

Abstract Natural killer (NK) cells are an important component of the innate immune system and play critical roles in host defense against infections and tumors. Accumulating studies have shown that the NK cell pool is highly heterogeneous, consisting of different cell subsets with distinct phenotypic and functional features. Recently, in collaboration with Professor Wayne Yokoyama, we showed that a novel NK cell subset expressing CD49a and lacking DX5 rarely recirculates and selectively resides in the liver, that is, liver-resident NK cells. While bone marrow (BM) cells are efficient in generating conventional (cNK) cells, the frequency of liver-resident NK cells is significantly reduced after BM transplantation. Conversely, lethally irradiated mice adoptively transferred with fetal liver cells exhibit normal frequency of liver-resident NK cells. Further analyses reveal that the adult liver retains hematopoietic potential and contains a few hematopoietic progenitor cells (HPCs), which are phenotypically distinct from BM lineage (Lin)-negative progenitor cells but resemble fetal liver counterparts. Moreover, adoptive transfer of these adult liver HPCs have the capacity to generate liver-resident NK cells, but not cNK cells. Finally, Liver HPCs express higher levels of the transcription factors that are essential for liver-resident NK cell development than their BM counterparts. Thus, our studies suggest an alternative development pathway for liver-resident NK cells.