**5. Regulatory B cells establish immunomodulatory environment for pregnancy**

With regard to their multi-faceted roles, B cells may participate in successful pregnancy [11]. A subtype of B cells named Bregs exhibits immunosuppressive function and therefore is considered an important players in immunological tolerance during pregnancy. During pregnancy, the change of the maternal immune response is governed by a range of cytokines that shape the type and abundance of leukocyte subsets in the decidua and placenta. In addition, these changes also include the reduction of antigen-presenting capacities of monocytes, macrophages, and DCs; inhibition of NK cells, T cells, and B cells; proliferation of dNK cells; maintenance of tolerogenic DCs; and the induction of Tregs [133].

Regulatory roles of Bregs were attributed exclusively to the production of the antiinflammatory cytokine interleukin-10 [23, 29, 134], even recent data have identified other B cell subsets with regulatory functions without IL-10 production. Indeed,

#### *Perspective Chapter: Role of Cytotrophoblast Cells and Placenta-Derived Exosomes… DOI: http://dx.doi.org/10.5772/intechopen.108335*

Bregs are cells that dampen ongoing inflammatory events in murine models [15] and counteract excessive pro-inflammatory responses during infection [14]. IL-10 is crucial for optimal pregnancy outcomes, Therefore IL-10 deficiency is related to fetal resorption, growth restriction, and even death of mother and child [135, 136]. This antiinflammatory cytokine is found in high levels in the decidual and placenta during pregnancy and is involved in damping the pro-inflammatory cytokine response. Interesting fact, at the beginning of pregnancy, the inflammation induced by the recognition of paternal antigens is upset by the production of IL-10 [137].

Bregs proportion increases during pregnancy and *in postpartum* [138] and firsttrimester peripheral blood-derived Bregs are shown to inhibit TNF-α secretion by activated T effector cells [139]. In the context of pregnancy, Bregs seem to be well positioned to perform the mechanisms that accommodate the growing semiallogeneic fetus and also allow the adequate immune response to the pathogen [10]. However, the mechanism of action of Bregs during pregnancy remains curtailed even if their importance in pregnancy has been shown in mouse models [138].

In order to allow a successful placentation and suitable fetal development, the maternal immune system undergoes several changes while allowing the mother to defend herself against infections [10]. A German group has developed a PE mouse model by transferring activated Th1-like splenocytes into normal pregnant mice and has demonstrated that pregnancy-associated immuno-regulation involved a shift from inflammatory toward anti-inflammatory immune responses mainly controlled by T and B cells [140, 141]. They have reported that Bregs were active players in the maintenance of pregnancy by modulating T cell functions [142]. Indeed, they have shown that Bregs transfer from normal pregnant to abortion-prone mice early in pregnancy prevents fetal rejection and restores pregnancy tolerance in mice [17].

The action of Bregs during pregnancy is interconnected with that of Tregs and DCs, providing an appropriate environment for fetal growth.

As described above, both Tregs and DCs play critical roles in determining pregnancy outcomes. In normal pregnancy, fetal-tolerant involves decidual DCs that remain immature and knew as tolerogenic DCs [143]. Tregs are also crucial players in maintaining maternal-fetal immune tolerance. At the onset of embryo implantation, expansion of the Tregs population improves the outcome of pregnancy whereas deficiency or low numbers of Tregs in the uterus during pregnancy leads to pregnancy lost (i.e., abortion or miscarriage) [22, 144].

As anti-inflammatory signal such as IL-10 or TGF-β is crucial to maintain the DC immature phenotype that prevents the activation of T cells [145], IL-10 and or TGF-β must then be initially: 1- present in the uterus and placenta to either drive the induction of immune tolerant DCs followed by the induction of Tregs, or 2- directly drive the induction of Tregs.

Overall Breg's role in pregnancy seems to be upstream to that of Tregs [17] and therefore, Bregs seem to be the first sources of IL-10 and TGF-β [10, 17].
