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Review
. 2014 Jul 7:5:106.
doi: 10.3389/fendo.2014.00106. eCollection 2014.

The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy

Barbara Polese  1 , Virginie Gridelet  1 , Eleni Araklioti  1 , Henri Martens  1 , Sophie Perrier d'Hauterive  1 , Vincent Geenen  1
Affiliations
Review

The Endocrine Milieu and CD4 T-Lymphocyte Polarization during Pregnancy

Barbara Polese et al. Front Endocrinol (Lausanne). .

Abstract

Acceptance of the fetal semi-allograft by the mother's immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse.

Keywords: T helper 17 cells; estradiol; human chorionic gonadotropin; luteinizing hormone; pregnancy; progesterone; regulatory T cells.

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Figures

Figure 1
Figure 1
Pregnancy hormones and CD4+ T cells blood levels during human pregnancy. hCG is an embryonic signal that announces the presence of an embryo to the maternal organism. hCG gene is transcribed as early as the eight-cells stage but it cannot be detected in the maternal blood before the second week after fertilization. Blood hCG concentration reaches a peak between the 8th and 11th week then it declines and stays low until the end of pregnancy. E2 is mainly produced by ovarian granulosa cells and by placenta. E2 concentration in maternal blood increases gradually after the first week, reaches a peak before parturition then drops few days after. Secreted mainly by corpus luteum then by placenta after 12 weeks of pregnancy, small quantities of P4 are already produced at the follicle stage. Then, P4 concentration in the blood increases strongly during the course of pregnancy to reach a peak before parturition. Relative blood levels of CD4+ T cells are compiled from different articles. During healthy pregnancy, Th1 cells are downregulated while Th2 cells are upregulated (13). Th2 predominance is considered to be essential for fetal survival. Pregnancy is also associated with a systemic expansion of Treg cells. The level of Treg cells is on the peak during the second trimester (14, 15). The circulating level of Th17 cell does not vary during human pregnancy and stays low (16). They are decreased during pregnancy when compared to non-pregnant women (17).
Figure 2
Figure 2
hCG and LH functions during human and murine pregnancy. Besides its endocrine role, hCG also acts on endometrial cells in a paracrine way and induces morphological and functional differentiation of endometrial stromal cells into decidua. hCG controls LIF and IL-6 secretion by human endometrial cells. By promoting angiogenesis, vasculogenesis, and angiogenic molecules production, hCG allows placenta to have adequate blood supply during the invasion of uterus and optimum nutrition to the fetus. The immunomodulatory properties of hCG are multiple. hCG has a positive impact on uNK cells, regulating their proliferation, putatively via mannose receptor (MR). Furthermore, hCG induces macrophage function, influences dendritic cell differentiation and function, and inhibits Th1 cells. Finally, hCG attracts Treg cells during early pregnancy and increases their frequency and suppressive activity. LH and hCG share the same LHCG receptor but LH is the only ligand of LHCG-R in mouse. hCG and LH are distinct molecules and actions of hCG cannot be claimed for LH. Murine blastocysts express the Lh gene and produce a bioactive LH signal thus showing that LH could be an important actor for the early dialog between the murine embryo and its mother. Data about the immunomodulatory roles of LH are scarce. LH could contribute to fetal tolerance by acting on murine Treg cells, similarly to hCG. LH would have also an impact on uNK cell recruitment.
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