Autologous induced pluripotent stem cells11/19/2023 Significant differences between CD107a - and CD107a + NK cells are indicated (n = 26, *** P<0.001, ** P<0.01, t-test after Bonferroni-Holm correction). In the right panel a summary of means and the SEM of the MFI of NKG2D, NKG2A, DNAM-1, and KIR on all NK cells exposed to the hiPSCs as well as CD107a - and CD107a + NK cells is shown. (C) In the left panel a summary of means and the SEM of NKG2D +, NKG2A +, DNAM-1 +, and KIR + cells among all NK cells exposed to the hiPSCs as well as CD107a - and CD107a + NK cells is shown. (B) A summary of means and the SEM of CD107a + NK cells of donors 4, 5, and 7 after exposure to three hiPSC lines (D1-iPSC4, D2-iPSC1, D6-iPSC2) and K562 cells is shown (n = 3). The KIR staining was performed with a mixture of all anti-KIR mAbs indicated in Table 1 to cover all KIR molecules. Among the CD107a + NK cells 53.0% were KIR positive. 46.7% of the CD107a - NK cells were KIR positive. After co-culture with target cells for 2 h 25.2% of the CD56 + NK cells expressed CD107a at the plasma membrane. Without contact to hiPSCs only 2.9% of the NK cells expressed the degranulation marker CD107a. (A) The degranulation of IL-2-activated NK cells of donor 7 in response to D6-iPSC2 cells is shown. (F) A summary of means of specific lysis and the SEM of the autologous hiPSC line D3-iPSC3 and the two allogeneic hiPSC lines (D1-iPSC4, D2-iPSC1) by NK cells of donor 3 is shown. (E) A summary of means of specific lysis and the SEM of D3-iPSC3 by allogeneic (allo) and autologous (auto) NK cells is shown. (D) A summary of means of specific lysis and the SEM of the autologous hiPSC line D2-iPSC1 and the two allogeneic hiPSC lines (D1-iPSC4, D3-iPSC3) by NK cells of donor 2 is shown. (C) A summary of means of specific lysis and the SEM of D2-iPSC1 cells by allogeneic (allo) and autologous (auto) NK cells is shown. (B) A summary of means of specific lysis and the SEM of the autologous hiPSC line D1-iPSC4 and the two allogeneic hiPSC lines (D2-iPSC1, D3-iPSC3) by NK cells of donor 1 is shown. The numbers of individual experiments (n) are indicated in the figure. (A) A summary of means of specific lysis and the SEM of D1-iPSC4 cells by allogeneic (allo) and autologous (auto) NK cells is shown. Therefore, NK cells might reduce the risk of teratoma formation even after autologous transplantations of pluripotent stem cell-derived grafts that contain traces of pluripotent cells. Thus, the susceptibility to NK cell killing appears to constitute a common feature of hiPSCs. Low amounts of human leukocyte antigen (HLA) class I proteins, which serve as ligands for inhibitory and activating NK receptors were also detected. The DNAM-1 ligands CD112 and CD155 as well as the NKG2D ligands MICA and MICB were expressed on the hiPSC lines. Killing was partly dependent on the activating NK receptor DNAM-1 (P = 8.22 x 10(-7)). The hiPSC lines were killed by both allogeneic and autologous NK cells although autologous NK cells were less efficient (P=8.63 x 10(-6)). Notably, the specific lysis of the individual hiPSC lines by IL-2-activated NK cells was significantly different (P = 1.72 x 10(-6)) and ranged between 46 % and 64 % in 51Cr-release assays when compared to K562 cells. IL-2-activated, in contrast to resting NK cells killed hiPSC lines efficiently (P = 1.69 x 10(-39)). We have analyzed the susceptibility of hiPSC lines to allogeneic and autologous natural killer (NK) cells. However, iPSC-derived grafts are at risk of giving rise to teratomas in the host, if residuals of tumorigenic cells are not rejected by the recipient. Human induced pluripotent stem cells (hiPSCs) could be used to generate autologous cells for therapeutic purposes, which are expected to be tolerated by the recipient.
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