Synergies of Extracellular Vesicles and Microchimerism in Promoting Immunotolerance During Pregnancy

Abstract

The concept of biological identity has been traditionally a central issue in immunology. The assumption that entities foreign to a specific organism should be rejected by its immune system, while self-entities do not trigger an immune response is challenged by the expanded immunotolerance observed in pregnancy. To explain this "immunological paradox", as it was first called by Sir Peter Medawar, several mechanisms have been described in the last decades. Among them, the intentional transfer and retention of small amounts of cells between a mother and her child have gained back attention. These microchimeric cells contribute to expanding allotolerance in both organisms and enhancing genetic fitness, but they could also provoke aberrant alloimmune activation. Understanding the mechanisms used by microchimeric cells to exert their function in pregnancy has proven to be challenging as per definition they are extremely rare. Profiting from studies in the field of transplantation and cancer research, a synergistic effect of microchimerism and cellular communication based on the secretion of extracellular vesicles (EVs) has begun to be unveiled. EVs are already known to play a pivotal role in feto-maternal tolerance by transferring cargo from fetal to maternal immune cells to reshape their function. A further aspect of EVs is their function in antigen presentation either directly or on the surface of recipient cells. Here, we review the current understanding of microchimerism in the feto-maternal tolerance during human pregnancy and the potential role of EVs in mediating the allorecognition and tropism of microchimeric cells.

Keywords: allorecognition; cross-dressing; extracellular vesicles (EV); immunotolerance; microchimerism; pregnancy.

Figure 1

Structure and immunological functions of fetal EVs in pregnancy. Fetal cells, including endothelial, immune, dendritic, and CTB cells, and especially STB, release great amounts of EVs to the maternal circulation. Upper: EV surface and internal cargo. Middle: Fetal EVs transfer their cargo to maternal immune cells by different mechanisms including endocytosis, phagocytosis and membrane fusion. Lower: EVs can act as APCs directly interacting with maternal T cells and trigger immunotolerance or activation. STB, syncytiotrophoblast; CTB, cytotrophoblast; IC, immune cell; EC, endothelial cells; DC, dendritic cells. For the sake of clear illustration, the size of structures is not displayed in realistic proportions. The figure was drawn using pictures from (http://smart.servier.com/).

Figure 2

Potential scenarios of EV involvement in the fetal allorecognition by maternal T cells. Maternal cells are shown in blue and fetal cells and EVs are shown in red. Up: Direct pathway. Fetal APCs, which secrete EVs to the intercellular space, present peptides (auto- or alloantigens) via MHC (I or II) molecules to immunocompetent maternal T cells. Middle: In the semi-direct pathway, fetal allogeneic MHC molecules (I or II) are acquired via capture and uptake of fetal cells (entire or only their cell membrane) or their secreted EVs, and then recycled and expressed on the maternal APC surface. APC can present antigens bound to fetal MHC molecules to maternal T cell receptors. The indirect pathway implies the processing of fetal proteins from EVs or cells and the presentation of deriving peptides by maternal MHC II complexes to T maternal cells. Down: Fetal-derived EVs cross-decorate maternal APCs with intact MHC-peptide complexes that can be recognized by T cells similar to the semi-direct pathway. All displayed processes involve co-stimulatory interactions between APCs and T cells which are decisive for subsequent reactions, which may be tolerogenic, immunoregulatory or –stimulatory. The figure was drawn using pictures from (http://smart.servier.com/) and was based on previous revisions (5, 116).

Figure 3

Proposed supportive effect of fetal EVs on microchimerism during pregnancy. 1. Fetal EVs are secreted mainly by the placenta and reach the maternal circulation. 2. Fetal EVs are taken up by endothelial cells (EC), alter their morphology and function, and cause vessel permeabilization. 3. EVs can also reach distant organs, influence their immune cell environment and induce changes in their extracellular matrix (ECM). 4. Fetal cells can trespass the placental barrier and access maternal vessels. 5. Profiting from the EC alterations, fetal cells can extravasate maternal vessels and 6. Access the parenchyma of distant organs as microchimeric cells. Processes indicated with a red question mark are yet to be confirmed. The figure was drawn using pictures from (http://smart.servier.com/).