Unravelling the Role of Trophoblastic-Derived Extracellular Vesicles in Regulatory T Cell Differentiation

Abstract

Regulatory T cells (Treg) are mandatory elements in the maintenance of human pregnancy, but their de novo differentiation has not been completely exposed. HSPE1 chaperone expressing trophoblast cells may have a role in it. Trophoblast-derived extracellular vesicles (EVs), either at the feto–maternal interface or in circulation, target CD4+ T cells. We hypothesized that HSPE1-associated trophoblastic cell line (BeWo)-derived EVs are active mediators of Treg cell differentiation. We proved at first that recombinant HSPE1 promote human Treg cell differentiation in vitro. Developing a CRISPR-Cas9 based HSPE1 knockout BeWo cell line we could also demonstrate, that EV-associated HSPE1 induces Treg development. Next-generation sequencing of miRNA cargo of BeWo-EVs characterized the regulatory processes of Treg polarization. By the use of single-cell transcriptomics analysis, seven Treg cell subtypes were distinguished and we demonstrated for the first time that the expression level of HSPE1 was Treg subtype dependent, and CAPG expression is characteristic to memory phenotype of T cells. Our data indicate that HSPE1 and CAPG may be used as markers for identification of Treg subtypes. Our results suggest, that trophoblastic-derived iEVs-associated HSPE1 and miRNA cargo have an important role in Treg cell expansion in vitro and HSPE1 is a useful marker of Treg subtype characterization.

Exosomes as Messengers between Mother and Fetus in Pregnancy

“…Trophoblast-derived EVs were further shown to induce the differentiation of T cells into Treg (regulatory T) cells [55]. Treg cells exert a strong antigen-specific immunosuppression [47].…”

“…Treg cells exert a strong antigen-specific immunosuppression [47]. The Treg induction was mediated by HSPE1 (heat shock 10kDa protein 1) carried by the EVs [55].…”

The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer

“…Interestingly, this study demonstrated the presence of FasL and TRAIL arranged in aggregates on exosome surfaces which can relay death signals to interacting cells including T cells in vitro [ 87 ]. Further skewing T cell function toward an inhibitory phenotype, EVs released from BeWo cells, a choriocarcinoma cell line used to model trophoblast cells, promote differentiation of helper T cells to T regs and expansion of these anti-inflammatory cells through 10 kDa Heat Shock Protein expression [ 88 ].…”

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…However, this effect is not observed in syncytin‐2 (Syn‐2)‐silenced VCT exosomes, indicating an important function of exosomal Syn‐2 in immune suppression . Kovacs et al suggest that trophoblastic EVs act as important players in immune tolerance, which is associated with their regulation of T reg differentiation. Extracellular vesicle‐derived heat shock protein family E member 1 (HSPE1) promotes T reg differentiation from CD4 + T cells and T reg cell expansion in vitro .…”