New Paradigm in the Role of Regulatory T Cells During Pregnancy

Abstract

Semi-allogenic fetuses are not rejected by the maternal immune system because feto-maternal tolerance induced by CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells is established during pregnancy. Paternal antigen-specific Treg cells accumulate during pregnancy, and seminal plasma priming plays an important role in expanding paternal antigen-specific Treg cells in mouse models. Although paternal-antigen specific Treg cells have not been identified in humans, recent studies suggest that antigen-specific Treg cells exist and expand at the feto-maternal interface in humans. Studies have also revealed that reduction of decidual functional Treg cells occurs during miscarriage with normal fetal chromosomal content, whereas insufficient clonal expansion of decidual Treg cells is observed in preeclampsia. In this review, we will discuss the recent advances in the investigation of mechanisms underlying Treg cell-dependent maintenance of feto-maternal tolerance.

Keywords: miscarriage; preeclampsia; pregnancy; regulatory T cells; seminal plasma.

Figure 1

Immunological balance at the feto-maternal interface during early pregnancy. EVTs did not express polymorphic HLA-A, B whereas HLA-C and non-polymorphic HLA-E, G, and F were expressed. Maternal CD8⁺ T cells and NK cells can directly recognize paternal HLA-C and CD4⁺ T cells can indirectly recognize it. HLA- E and G protect EVTs from NK-cell mediated cytotoxicity. Treg cells can recognize fetal antigens via maternal antigen presenting cells (APCs) and induce tolerance in an antigen-specific manner. EVT, Extravillous trophoblast; NK, natural killer cell; Treg; regulatory T cell; APC, antigen-presenting cell.

Figure 2

Distribution of paternal antigen-specific Treg cells in mice. When a female mouse is mated with an allogenic male mouse, paternal antigen-specific Treg cells increase in the uterine-draining lymph nodes one day before implantation due to seminal plasma priming. After implantation, the paternal antigen-specific Treg cells population in the uterus increases day by day during the course of the pregnancy, but not in the peripheral lymph nodes and the spleen. APC, antigen-presenting cell.

Figure 3

Single-cell based TCR repertoire analysis method. To study the clonality of effector Treg cells, a single-cell based T cell receptor (TCR) repertoire analysis method was used. Paired samples of maternal peripheral blood mononuclear cells and decidual lymphocytes were obtained. CD4+CD25+CD45RA-CD127low/- effector Treg cells were single-cell sorted. The cDNAs of complementarity determining lesion 3 (CDR3) in TCRβ chain and FoxP3 were amplified by RT-PCR. The nucleotides and amino acid sequences of CDR3 were analyzed.

Figure 4

Distribution of clonally expanded effector Treg cells in humans. (A) Frequencies of total Treg cells, effector Treg cells and clonal populations of effector Treg cells in normal pregnancy. The systemic and local expansion of the Treg cells and effector Treg cells pool is observed during pregnancies in humans. Clonally expanded effector Treg cells increase in decidua, but not in peripheral blood. Clonal populations of effector Treg cells more increase in 3rd trimester than 1st trimester. (B) Clonally expanded decidual effector Treg cells in miscarriage and preeclampsia. In decidua, effector Treg cells pool decreased in miscarriage with normal chromosomal content than 1st trimester normal pregnancy, whereas the frequency of clonal populations of effector Treg cells does not significantly decrease. On the other hand, clonal populations of decidual effector Treg cells decreased preeclampsia than 3rd trimester normal pregnancies.

Figure 5

Pathological change in Treg cells during pregnancy in humans. During pregnancy, Treg cell pools both in the peripheral blood and decidua expand. Clonally expanded effector Treg cells are observed only in the decidua, but not in the peripheral blood. Clonally expanded effector Treg cells are higher in the 3rd trimester than in the 1st trimester. In miscarriage cases with normal chromosomal fetal content, the number of decidual effector Treg cells decreases. On the other hand, clonal populations of decidual effector Treg cells decrease in cases of preeclampsia.