**Table 1.** *Cont.*

In vitro, MSC-exosomes exert an immunomodulatory function, mainly by regulating the commitment of immune cells or altering their inflammatory cytokine secretion profiles [28]. For example, in the presence of IFN-γ and TNF-α, MSCs generate exosomes that induce macrophages to switch from an M1- to an M2-like phenotype, and exosomal miRNAs, including miRNA-146 and miRNA-34, greatly contribute to this process [34]. Mechanistically, miRNA-146 upregulate expression of M2-associated genes such as *TRAF6* and *IRAK1* by targeting NF-κB signaling [53], and miRNA-34 targets *Notch1* to suppress transcription of genes encoding M1-related pro-inflammatory cytokines, such as IL-6 and TNF-α [54]. The MSC-exosomal miRNA-181a has been consistently found to enhance the production of M2-related cytokines, including IL-10 and TGF-β while reducing production of the M1-related cytokines TNF-α, IL-6 and IL-12 by macrophages [46,55]. In addition to altering the secretion profile of macrophages, miRNA-181a induces Treg cell generation by suppressing expression of the *c-Fos* gene, which functionally counteracts the Foxp3-dominant transcriptional program associated with Treg cell development [45]. Nevertheless, a coculture experiment revealed that Treg cell induction by MSC-exosomes was less efficient than that by MSCs, indicating that some other factors contribute to this process. In fact, soluble factors from MSCs, including IDO, PGE2 and IL-10 strongly induce Treg cell generation [56]; however, except for IL-10, they are not present in MSC-exosomes [28,50].

In vivo, MSC-exosomes control immunomodulatory processes in an antigen-presenting cell (APC)-mediated manner [52]. For example, dendritic cells (DCs) serve as critical mediators of the effects of MSC-exosomes on Treg induction. Mechanistically, MSC-exosomes induce mature DCs to acquire immune tolerogenic phenotypes [51]. A critical function of tolerogenic DCs is inducing Treg cell generation in vivo [57]. Tolerogenic DCs secrete high levels of anti-inflammatory cytokines, such as IL-10 and TGF-β, and express low levels of costimulatory molecules, thus inducing naïve CD4<sup>+</sup> T cells to commit to differentiation into Tregs [51]. In addition to DCs, MSC-exosomes are able to restrict B cell maturation, which decreases the production of immunoglobulin-G (IgG) [50,58]. To a certain extent, the above effects of MSC-exosomes will assist in attenuating the immune responses driven by other T subsets, such as Th1, Th2, Th17 cells or CD8<sup>+</sup> T cells [33,59–61] (Figure 1). Indeed, studies have shown that incubating mouse adipose tissue-derived MSC-exosomes with mouse splenic immunocytes in vitro significantly downregulates expression of genes encoding Tbx21, Gata3 and Rorc, which centrally control the commitment of Th1, Th2 and Th17 cells, respectively [47]. CD8<sup>+</sup> T cells that delivered human umbilical cord-derived MSC-exosomes to GVDH mice significantly decreased the number of CD8<sup>+</sup> T cells along with the ratio of CD8<sup>+</sup> T cells to CD4<sup>+</sup> T cells in the peripheral blood [59]. However, intriguingly, reduced numbers of CD4<sup>+</sup> or CD8<sup>+</sup> T cells did not occur when conditioned by MSC-exosomes in vitro, which suggests, at least, that MSC-exosomes modulate host immune responses independently of their direct effect on impairing the survival of CD4<sup>+</sup> or CD8<sup>+</sup> T cells [50] (Figure 1). In other words, the mechanisms by which MSC-exosomes induce immunomodulation in vivo are more complicated than those observed in vitro, and the details need to be further elucidated.

**Figure 1.** MSC-exosomes exert anti-inflammatory and immunomodulatory effects, which aid in attenuating tissue cell damage. MSC-exosomes perform these functions mainly through interaction of exosomal miRNAs and APCs. They can induce immature and mature DCs to differentiate into tolerogenic DCs, mediating naïve CD4<sup>+</sup> T cell differentiation into Tregs. In addition, MSC-exosomes are able to induce macrophages to transform from the M1 to the M2 phenotype while enhancing secretion of M2-related cytokines such as IL-10 and TGF-β and decreasing M1-related cytokine TNF-α, IL-6 and IL-12 levels. With regard to B cells, MSC-exosomes inhibit the maturation and function of B lymphocytes and cause a decrease in IgG secretion. MSC-exosomes also decrease the CD8<sup>+</sup> T cell number and the CD8+/CD4<sup>+</sup> T cell ratio in the peripheral blood of in vivo mouse models.
