What is the role of regulatory T cells in the success of implantation and early pregnancy?

Abstract

Problem: The immune system is well controlled by the balance between immunostimulation and immunoregulation. CD4(+)CD25(+) regulatory T (Treg) cells and an enzyme called indoleamine-2, 3-dioxygenase (IDO) mediate maternal tolerance of the allogeneic fetus. Treg cells, therefore, may prevent early pregnancy loss due to maternal 'rejection.'

Methods: The latest understanding of tolerance during pregnancy is reviewed.

Results and conclusions: Recent data show that CD4(+)CD25(+) Treg cells play essential roles in the induction and maintenance of tolerance, and that they augment the IDO activity in dendritic cells and macrophages. Therefore, CD4(+)CD25(+) Treg cells and IDO enzyme may cooperate in the induction of tolerance during pregnancy. Treg deficiency is associated with very early post-implantation loss and spontaneous abortion in animal models, and low Treg levels are associated with recurrent miscarriages in humans.

Fig. 1

Induction of maternal MHC antigen-specific tolerance during pregnancy in human. Villous trophoblasts do not express MHC class I antigens or MHC class II antigens, but MHC class II antigens such as HLA-DR, and DQ are expressed on the endoplasmic reticulum (ER) in trophoblastic cell debris. These antigens may be presented by maternal dendritic cells, and activated maternal CD8⁺ T cells may be deleted by sHLA-G₁ or the Fas/Fas ligand system. On the other hand, fetal antigen-recognized maternal CD4⁺ T cells may differentiate to CD4⁺CD25⁺ Treg cells. Furthermore, CEA associated with CD1d on trophoblasts may induce regulatory CD8⁺ T cells, and PD-L1 on trophoblasts may induce tolerance by the PD-L1/PD-1 system

Fig. 2

The role of CD4⁺CD25⁺ Treg cells in the induction of tolerance during pregnancy. When CD25⁺ cells are absent and conventional T cells are present, BALB/C nu/nu mice show abortion in an allogeneic pregnancy model, and show normal pregnancy in a syngeneic pregnancy model (a). In an abortion-prone model, adoptive transfer of CD4⁺CD25⁺ T cells from pregnant CBA/J mice on day 0 prevents abortion, but adoptive transfer of these CD4⁺CD25⁺ T cells on day 4.5 does not prevent abortion (b). Adoptive transfer of CD4⁺CD25⁺ T cells from non-pregnant mice on day 0 does not prevent abortion (b). Administration of an anti CD25 monoclonal antibody on day 0 induces abortion in an allogeneic pregnancy model (c)

Fig. 3

The mechanisms for immunoregulation by CD4⁺CD25⁺ Treg cells during pregnancy. As a first step, CD4⁺CD25⁺ Treg cells are activated by T cell receptor (TCR) system and CD28-B7 co-stimulatory system. These activated CD4⁺CD25⁺ Treg cells express CTLA-4 and CCR5 on their surface, and have an ability for immunoregulation. CCR5⁺ Treg cells infiltrate toward sites of inflammation such as the feto-maternal interface. CD4⁺CD25⁺ Treg cells manifest immunoregulation by up-regulation of IDO in APCs, cell-to-cell interaction through membrane TGF-β1, LAG-3, PD-1 and surface galectin-1 or immunoregulatory cytokines such as TGF-β and IL-10