| Abstract |
Immune overactivation damages tissues in T cell-mediated disorders, and cell-based therapies are being developed to suppress T cell responses. Mesenchymal stromal cells (MSCs) modulate immunity; however, their suppressive effects depend on inflammatory cytokine priming. Umbilical cord-derived MSCs are attractive for non-invasive collection and expansion, but their effects diminish after intravenous infusion. PD-1/PD-L1 signaling lowers T cell activation; therefore, soluble PD-L1 (sPD-L1)-secreting MSCs may provide contact-independent checkpoint engagement and we tested whether sPD-L1-MSCs can modulate an established human T-cell response in vivo. Using a model in which human peripheral blood mononuclear cells were transferred into immunodeficient NOG mice, umbilical cord- or bone marrow-derived MSCs did not restrain established T cell activation, whereas sPD-L1-MSCs transiently blunted activation during dosing without reducing T cell numbers. In vitro, a neutralizing anti-PD-L1 antibody partially relieved this effect at early time points, consistent with PD-1/PD-L1 signaling involvement. Biodistribution imaging and ELISA showed predominant pulmonary trapping and short-lived sPD-L1 exposure after intravenous MSC administration. This limited and transient exposure may contribute to the variability in MSC-based immunomodulation. Therefore, in this late-intervention xenogeneic model, the timing, location, and magnitude of exposure to MSC-derived mediators strongly constrain efficacy, and checkpoint delivery from engineered MSCs can provide transient immunomodulatory activity.
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