ИСТИНА

The crucial problem of modern transplantology is the donor organ shortage crisis. The use of patient-specific induced pluripotent stem cells (iPSCs) offers the opportunity of personalized therapy without a lifelong regimen of immunosuppressive drugs. However, there are some reports pointing the immune response to syngenic and autologous iPSC-derivatives. This issue raises concerns regarding the complete immunological tolerance of autologous iPSC-derivatives. Our study is dedicated to the study of NK-cell response against various iPSC-derivatives. According to the “missing-self” hypothesis, the major function of NK-cells is the recognition of cells lacking self HLA class I molecules. Here we report that fibroblast- and chondrocyte-like cells differentiated from iPSCs provoked the degranulation of autologous NK-cell lytic granules. Comparable high level of NK-cell activation was elicited by isogenic iPSC-derivatives with knockout of the B2M gene that do not express HLA-I proteins. At the same time, the initial isogenic skin fibroblasts used to obtain iPSCs nearly did not trigger NK-cell cytotoxicity. Thus, we assumed that the differentiation and following cultivation of iPSC-derivatives may negatively affect the balance of ligands for activating and inhibiting NK-cell receptors. We found that this balance in iPSC-derivatives was indeed violated. Compared with the initial somatic cells, the expression of HLA-I molecules in iPSC-derivatives was reduced, but the expression of ligands to the DNAM-1 and NKG2D activating receptors was increased. We have shown that pre-treatment of iPSC-derivatives with the proinflammatory cytokine IFNγ increases the expression of HLA-I molecules, which leads to a decrease in the activation of NK-cells. In this regard, the balance of ligands for NK-cell receptors should be taken into account in iPSC-based cell therapies. This work was supported by the RFBR (grants #20-315-90041 and #19-29-04113-mk).