Objective: The aim of this study was to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSC) derived exosomes (Exo) on the activity and function of umbilical cord blood-derived regulatory T cells (hUCB-Treg) after adoptive transfer in mice, and to further explore the related molecular mechanisms.

Methods: The Xenograft-versus-host disease (X-GVHD) model of NCG mice were established by caudal vein infusion with human PBMC. Mice were treated with PBS, Treg, Exo and Treg+Exo, respectively. The body weight, hair and survival status of the mice were observed. The pathological changes of target organs, the proportion of human T cells and Tregs in the blood of mice, the concentration of IL-17a and IL-10 in serum was used to determine the incidence of X-GVHD in each group.

Results: In the X-GVHD model of NCG mice, compared between the Exo group vs. the PBS group, Treg+Exo group vs. Treg group, the survival time of mice treated with Exo was significantly prolonged, and the evaluation of clinical score showed that the symptoms of X-GVHD were reduced (asthenia, arched back, and hair removal, etc). Pathological lesions in target organs (lung, liver, spleen, intestine, and skin) were improved and inflammatory cell infiltration was reduced in the mice treated with Exo, to further enhance the efficacy of Treg treatment. At the same time, Exo treatment increased the proportion of Treg and CD4+T cells in peripheral blood, decreased the content of CD8+T cells, with reducing the level of inflammatory factors in plasma to a certain extent.

Conclusion: Exo treatment enhanced the effect of Treg on inhibiting X-GVHD by reducing inflammatory cell infiltration in target organs, increasing Treg cell recruitment and regulating cytokine secretion.