Effect of mesenchymal stromal cells on cytotoxic signaling pathway in natural killer cells.

摘要

Given the increasing use of mesenchymal stromal cells (MSCs) and natural killer (NK) cells in cell therapy protocols, we investigated the immunomodulatory effect of MSCs on two NK cell lines, KHYG-1 and NK-92, by co-culture with cell-contact or in a transwell system, or with MSC-conditioned medium. NK cytotoxicity was measured by 51Cr release assay. NK immunophenotype and phosphorylation of extracellular signal-regulated kinase (ERK) were assessed by flow cytometry. Granule polarization in NK cells was analyzed by immunostaining of perforin using confocal microscopy. We found that MSCs suppressed NK cytotoxicity mainly via soluble factors, including nitric oxide (NO) and the indoleamine 2,3-dioxygenase (IDO) catabolite, kynurenine. Prostaglandin E2 (PGE2) worked only synergistically with IDO. MSCs were lysed by NK-92 but not KHYG-1, possibly due to upregulation of CD94 and CD244 and increased granule polarization in NK-92. These results demonstrate that MSCs can suppress the cytotoxicity of NK cell lines but can also be targets of NK-mediated cytolysis; thus, these considerations must be taken into account when designing clinical protocols with MSCs or NK cell lines.