Human Fetal Liver Mesenchymal Stem Cell-Derived Exosomes Impair Natural Killer Cell Function

Mesenchymal stem cells (MSCs) are powerful immunomodulators that regulate the diverse functions of immune cells involved in allogeneic reactions, such as T cells and natural killer (NK) cells, through cell-cell contact or secreted factors. Exosomes secreted by MSCs may be involved in their regulatory functions, providing new therapeutic tools. Here, we showed that fetal liver (FL) MSC-derived exosomes inhibit proliferation, activation, and cytotoxicity of NK cells. Exosomes bearing latency associated peptide (LAP), TGFβ, and thrombospondin 1 (TSP1), a regulatory molecule for TGFβ, induced downstream TGFβ/Smad2/3 signaling in NK cells. The inhibition of TGFβ, using a neutralizing anti-TGFβ antibody, restored NK proliferation, differentiation, and cytotoxicity, demonstrating that FL-MSC-derived exosomes exert their inhibition on NK cell function via TGFβ. These results suggest that FL-MSC-derived exosomes regulate NK cell functions through exosome-associated TGFβ.