Differential Immunomodulatory Effects of Human Bone Marrow-Derived Mesenchymal Stromal Cells on Natural Killer Cells

Abstract

Mesenchymal stromal cells (MSCs) modulate immune responses through cell contact-dependent or paracrine mechanisms and are themselves known to have low immunogenicity. Given the increasing use of both natural killer (NK) cells and MSCs in cell-based therapies, we investigated the interaction between the two cell types using the NK cell lines, KHYG-1 and NK-92, and human bone marrow-derived MSCs. NK lines were cocultured with MSCs, either directly or in a transwell system, and the effects on proliferation, interferon-gamma (IFN-γ) production, and cytolytic activity of NK cells were analyzed. Cytotoxicity was measured in a 4 h chromium release assay. MSCs did not affect the proliferation of NK cell lines but reduced IFN-γ production by KHYG-1, but not NK-92, when cocultured directly at 10:1 NK:MSC ratio. MSCs suppressed K562 lysis by both KHYG-1 and NK-92 cells in contact-free transwell cocultures but only reduced cytotoxicity of KHYG-1 and not NK-92 cells when cells were in direct contact in coculture. Immunosuppressive effects of MSCs were mediated by indoleamine-2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) secreted by MSCs and were abrogated in the presence of IDO and PGE2 inhibitors. In the presence of MSCs, granule polarization was suppressed and induced respectively, in KHYG-1 and NK-92. Consistent with this, MSCs were susceptible to lysis by NK-92 but not KHYG-1. These studies indicate the differential crosstalk between MSCs and two highly cytotoxic NK lines and may be important when designing future cell therapy protocols with these two cell types.