Role of Progesterone in Regulatory T-cell development

The Immune System and Pregnancy

Figure 1:

Figure 1: Regulation of immune response at the maternal-fetal interface is critical for successful implantation of the embryo and successful pregnancy

At the onset of pregnancy the maternal immune system must go through many changes in order to maintain a successful pregnancy [1] due to the simple fact that the cells of the fetus have foreign antigens that would in normal circumstances cause a very strong immune response and lead to rejection of the foreign tissue (Figure 1). While the placenta serves as a local barrier between mother and fetus, it is known that fetal cells migrate out and can be found at quite high levels in the maternal blood, even years after pregnancy, a phenomenon called “microchimerism”[2]. Thus the mother’s immune system must have mechanisms to inhibit a reactive response to paternal antigens on the fetal cells. Previous research has shown that Regulatory T-cells (Tregs, discussed here) are greatly increased during pregnancy[3] and absence leads to rejection of the fetus.  However, the mechanism of these immune changes are not yet clear.

One potential hypothesis is that the change in hormones that occur at the onset of pregnancy aid in the maternal-fetal immune tolerance. The main hormones associated with pregnancy are estrogen and progesterone which both steadily increase and are largely produced by the placenta. Progesterone has been shown to be produced both by the placenta and umbilical cord erythrocytes[4]. It is clear that it is essential for pregnancy from studies in which progesterone receptors were blocked, which led to loss of the fetus[5]. This has been suggested to be immune mediated, and it has been shown previously that progesterone has an effect on dendritic cells, uterine natural killer cells and T-cells. The following study examines specifically the response of regulatory T-cells to progesterone in order to help elucidate the role of progesterone in the immune system.

Effect of Progesterone on the differentiation of Treg-cells from cord blood

The authors demonstrated that adding progesterone to the culture increases the number of FoxP3+ T-regulatory cells to comparable levels as the addition of a known inducer, TGF-β, and that the increase is even more pronounced when both are added to the culture (Figure 2A). A test for functionality of the Treg-cells (Figure 2B) was then performed using CFSE labeled target T-cells whose label becomes diluted each time the cell divides which is an indicator of T-cell activation and expansion (i.e the more the peaks move to the left the more the cells have divided and are thus activated). Since functional Tregs should be able to suppress target T-cells, these results suggest that P4 is superior to TGFB for inducign functional Tregs with suppresive properties. Additionally, Fig 2C establishes that the addition of a progesterone receptor inhibitor RU486, reduces FoxP3 mRNA levels to basal levels. Interestingly, the effect of progesterone was only potent in cord blood, not adult peripheral blood (Figure 2D)

Figure 2: Progesterone causes an increase in FoxP3+ T reg cells derived from Cord Blood

Progesterone promotes differentiation of memory Treg cells and supresses differentiation of TH17 cells

It was observed that memory Treg cells (CD45RA-/CD45RO+) were found at a much higher frequency in cord blood than peripheral blood(2A). Also, when treated with progesterone this number increased as much as 4x. They then looked at TH17 cells, which are quite different than Treg cells because instead of suppressing the immune response, they activate it. TGF-beta will cause both TH17 cells and Treg cells to be produced, however, this study found that progesterone will suppress differentiation into TH17 cells.

treg promotion th17 suppession

Figure 3: [A.] Cord blood is enriched for memory FoxP3+ cells compared to Adult peripheral blood.[B] Progesterone further increases the number of FoxP3+/ CD45RA-/CD45RO+ memory Treg cells. [C] Progesterone was found to suppress TH17 cell differentiation

Potential signalling pathways

 It is known that IL-2 activates STAT5 to induce regulatory T-cells and IL-6 activates STAT3 to induce TH17 cells[6] (Figure 4A), so the authors were curious if progesterone also worked through STAT5/STAT3 pathway. They found that in the absence of IL-2 or IL-6, there is no effect of progesterone on STAT5 or STAT3 activation, however, there was an increase in STAT5 activation in the prescense of IL-2, and a decrease in STAT3 in the presence of IL-6 (Figure 4B). This suggests that STAT3 and STAT5 are downstream targets of P4.

They next looked at global gene expression to determine which genes were affected by progesterone. Interestingly, they found that IL-6 receptor was greatly down regulated in the presence of progesterone(Figure 4C). This helps to explain why progesterone is TH17 suppressive since IL-6 receptor is necessary to activate STAT3 signalling.

signaling

Conclusions and critiques

Progesterone may be a better choice for in vitro induction of Treg cells as they appear to be more functionally active and may enrich the final population by suppressing TH17 cell differentiation. This paper helped to elucidate possible mechanisms involved in maternal fetal tolerance, however, it is yet to be determined the in vivo implications of these results. A mouse model that can have progesterone production induced or stopped at various stages in gestation would be very interesting and would have been a good addition to this paper. Additionally, adult peripheral blood collected from pregnant females would be a more accurate control to compare than non-pregnant individuals as the hormones present in the mother blood would likely have an effect and are also more closely matched to the hormones present in cord blood.

References

1. Hunt, J. S., Petroff, M. G., McIntire, R. H., & Ober, C. (n.d.). HLA-G and immune tolerance in pregnancy. Retrieved from http://www.fasebj.org/content/19/7/681/F1.expansion.html

2. El-Badri, N. S., & Groer, M. (2008). The Effect of Pregnancy on Production of Maternal Endogenous Hematopoietic Stem Cells. Bioscience Hypotheses, 1(2), 100–102. doi:10.1016/j.bihy.2008.02.012

3. Lee, J. H., Ulrich, B., Cho, J., Park, J., & Kim, C. H. (2011). Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. Journal of Immunology (Baltimore, Md. : 1950), 187(4), 1778–87. doi:10.4049/jimmunol.1003919

4. Lee, J. H., Ulrich, B., Cho, J., Park, J., & Kim, C. H. (2011). Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. Journal of Immunology (Baltimore, Md. : 1950), 187(4), 1778–87. doi:10.4049/jimmunol.1003919

5. Arck, P., Hansen, P. J., Mulac Jericevic, B., Piccinni, M.-P., & Szekeres-Bartho, J. (2007). Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. American Journal of Reproductive Immunology (New York, N.Y. : 1989), 58(3), 268–79. doi:10.1111/j.1600-0897.2007.00512.x

6. http://www.cnic.es/en/inflamacion/moleculas/

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