Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.
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Natural killer (NK) cells act as innate immune cells against hepatitis C virus (HCV) infection. Interferon-α (IFN-α) and ribavirin are the standard treatments for patients with HCV infection. This study is aimed at investigating the dynamic changes in the frequency of different subsets of NK cells following treatment in xx chronic hepatitis C (CHC) patients. CHC patients were treated with peg-IFN or IFN-α, and followed up for 72 weeks. The frequency of different subsets of NK in CHC patients was determined longitudinally by flow cytometry. Treatment with the standard therapy increased the percentages of NKp30(+), NKp46(+), and CD107a(+) NK cells, which were positively correlated with the declining of serum HCV-RNA, but not IFN-γ(+) NK cells. NKG2A(+) and KIR2DL3(+) NK cells were associated with an early virological response in CHC patients. Treatment with IFN-α adjusts the balance of activated receptors and inhibitory receptors and enhances the cytotoxic activity of NK cells. Therefore, measuring NK subsets may be valuable for therapeutic responses in CHC patients.

Killer Ig-like receptors (KIR) and HLA class I ligands were studied in unrelated hemopoietic stem cell transplantation for chronic myeloid leukemia (n = 108). Significantly improved overall survival was observed in patients, which were homozygous for HLA-C-encoded group 1 (C1) ligands compared with those with group 2 (C2) ligands. Favorable outcome in the former patient group was an early effect that was highly significant in patients transplanted with G-CSF-mobilized peripheral blood and patients with advanced disease stages. In contrast, presence of C1 ligands in the donor was associated with significantly reduced patient survival. The differential roles of the two HLA-C ligands are explained in the context of a biased NK cell reconstitution, which is generally dominated by the presence of C1- but absence of C2-specific NK cells. The clinical observations are corroborated by in vitro experiments showing that NK cells derived from hemopoietic progenitor cells generally acquire the C1-specific inhibitory KIR2DL2/3 at earlier time points and with higher frequency than the C2-specific KIR2DL1. These findings define a novel determinant for understanding the role of NK cells in clinical hemopoietic stem cell transplantation.