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.
Highlights
During human pregnancy the maternal immune system has to fine balance itself, in order to develop and maintain immune tolerance toward the semi-allograft fetus
On the basis of these data, we hypothesized that trophoblast-derived extracellular vesicles (EVs)-associated HSPE1 and miRNA cargo specify the generation and heterogeneity of Treg cells at the feto–maternal interface
We identified by mass spectrometry 81 proteins in intermediate-sized EVs (iEV) and 31 proteins in the sized EVs (sEV) fraction
Summary
During human pregnancy the maternal immune system has to fine balance itself, in order to develop and maintain immune tolerance toward the semi-allograft fetus. Treg cells are found at high levels in decidual tissues, and recently it has been described that in vitro co-culture of extravillous trophoblast cells with blood derived CD4+ T cells induces Treg cell differentiation [4]. It has not been clearly demonstrated what mechanisms are involved in the de novo differentiation of Treg cells at the feto–maternal interface [5,6]. On the basis of these data, we hypothesized that trophoblast-derived EV-associated HSPE1 and miRNA cargo specify the generation and heterogeneity of Treg cells at the feto–maternal interface
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