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.
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