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Review
. 2014 Aug 21:5:389.
doi: 10.3389/fimmu.2014.00389. eCollection 2014.

Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions

Maria Grazia Ruocco  1 , Gérard Chaouat  2 , Laura Florez  1 , Armand Bensussan  2 , David Klatzmann  3
Affiliations
Review

Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions

Maria Grazia Ruocco et al. Front Immunol. .

Abstract

In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.

Keywords: NK cells; Treg; cancer tolerance; evolution of the immune system; suppressor T-cells.

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Figures

Figure 1
Figure 1
Tregs in mouse pregnancy. Thymic Tregs (tTregs) recognizing maternal/fetal self-antigens differentiate in the thymus from the CD4+ T-cell precursors by up-regulating Foxp3 expression. During the estrus cycle, there is an increase in tTregs in the periphery and the uterus where, together with tolerogenic dendritic cells (tDC) and uterine NK (uNK) cells, they prepare a uterine tolerogenic environment for pregnancy under a hormonal control. During the estrus phase, recruitment of tTregs at ovulation is maximum in order to prepare a tolerogenic uterine environment for a potential embryo implantation. During pregnancy, self-antigen-specific activated/memory tTregs mount a first-line tolerogenic response (28). Later, the first fetal/paternal alloantigens generated by fetal cells trigger an immune response to paternal alloantigens (85). Alloantigen presentation through tDCs favors the conversion of naïve CD4+ T-cells in induced peripheral Tregs (pTregs) by up-regulating Foxp3 and its Cigs1 enhancer gene expression (84). The clonal expansions of allospecific pTregs together with the proliferation of tTregs, uNKs, and tDCs during the mid-gestation periods ensure the maintenance of immune tolerance to the fetus and allow vascularization to guarantee a steady supply of nutrients and oxygen to the fetus for a proper growth and development. Generation of memory pTregs specific for paternal antigens will contribute to tolerance induction to the same fetal/paternal alloantigen exposure in case of a secondary pregnancy with the same paternal antigens. The tTregs, uNKs, and tDCs cross-talk is yet poorly defined.
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