Citation Leber A, Teles A, Zenclussen AC Regulatory T cells and their role in pregnancy Am J Reprod Immunol 2010

Regulatory T cells emerge in the last years as key players in allowing fetal survival within the maternal uterus They were shown to be a unique subpopulation of T cells expanding during human and murine pregnancy The importance of Treg for a normal pregnancy situation was proven by studies showing that their absence impairs murine pregnancy while the adoptive transfer of Treg prevents fetal rejection In humans, pregnancy pathologies are associated with lower Treg frequencies while therapies that improve pregnancy outcome are able to boost their number Functional studies have shown that Treg can regulate immune cell responses directly at the fetal–maternal interface either by interacting with other cells or by inducing the expression of immune regulatory molecules This article revises relevant literature on regulatory T cells in human and murine pregnancy

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0897.2010.00821.x

Regulatory T cells and their role in pregnancy.

The CD4+CD25bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage

Trophoblast debris modulates the expression of immune proteins in macrophages: a key to maternal tolerance of the fetal allograft?

Several types of T cells have been associated with the pathogenesis of unexplained recurrent spontaneous abortion (URSA), including Th1/Th2/Th17/Tregs cell. It has been appreciated that immunotherapy with paternal or third party lymphocytes is an effective method of treatment for URSA patients. The balance of Th1/Th2 cells could be maintained and an increase of Treg cells would be beneficial after immunotherapy; however, the mechanism by which the Th17/Treg balance affects URSA has not yet been fully elucidated. Here, we used flow cytometry, liquid chip technology and quantitative real-time PCR (qPCR) methods to characterize Th17/Treg cell populations after immunotherapy. We found that after immunotherapy in URSA patients, the percentage of Th17 cells decreased and the percentage of Treg cells in peripheral blood mononuclear cells (PBMC) increased, as detected by flow cytometry. Immunotherapy may induce a decrease in the Th17/Treg ratio and the Treg bias, which may be beneficial for the maintenance of pregnancy. The expression level of ROR gamma t, a transcription factor found in Th17 cells, decreased and the expression of the Treg-specific transcription factor Foxp3 increased in peripheral blood as detected by qPCR. Immunotherapy may induce a decrease in the ratio of ROR gamma t to Foxp3 and a Treg cell bias, which would be beneficial for pregnancy maintenance. The secretion of the Treg-associated cytokine TGF-beta, as well as Th2 cytokines, was increased in serum, while the secretion of Th17-associated cytokine IL-17A and Th1 cytokine production was decreased. The Th1/Th2 cytokine ratio significantly decreased. Similarly, the Th17/Treg ratio significantly decreased in the total patient after immunotherapy. These results indicate that in patients with URSA, immunotherapy with mononuclear cells derived from the baby’s father could affect both Th1/Th2 and Th17/Treg balance, and we found that the Th2 and Treg bias would be beneficial for pregnancy, which may lead to a balancing of the Th17/Treg ratio in URSA patients after immunotherapy.

/pdf/alteration-of-th17-and-treg-cells-in-patients-with-20xs377s3y.pdf

Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy

Clinical application of expanded CD4+25+ cells.

The embryo expresses paternal Ags foreign to the mother and therefore has been viewed as an allograft. It has been shown that anergic T cells generated by blocking of the CD28/B7 costimulatory pathway with anti B7-1 and anti B7-2 mAbs can be transferred as suppresser cells to prevent allograft rejection. Little is known, however, about the in vivo function of anti-B7-treated T cells after their transfer into abortion-prone mice in the maintenance of materno-fetal tolerance. In the present study, abortion-prone CBA/J females mated with DBA/2 males were administered anti-B7-1 and anti-B7-2 mAbs on day 4 of gestation (murine implantation window). The anti-B7-treated T cells subsequently were adoptively transferred into abortion-prone CBA/J mice. We demonstrated that costimulation blockade with anti-B7 mAbs at the time of implantation resulted in altered allogeneic T cell response and overcame increased maternal rejection to the fetus in the CBA/JxDBA/2 system. The transferred anti-B7-treated T cells appeared to be regulatory, decreasing responsiveness and generating clonal deviation in maternal recipient T cells. The transferred CFSE-labeled T cells were found to reside in the spleen and uterine draining lymph nodes, and a few were localized to the materno-fetal interface of the maternal recipient. Our findings suggest that the anti-B7-treated T cells not only function as potent suppresser cells, but also exert an immunoregulatory effect on the maternal recipient T cells, which cosuppresses maternal rejection to the fetus. This procedure might be considered potentially useful for fetal survival when used as an immunotherapy for human recurrent spontaneous abortion.

/pdf/adoptive-transfer-of-paternal-antigen-hyporesponsive-t-cells-fgxxajbd40.pdf

Adoptive Transfer of Paternal Antigen-Hyporesponsive T Cells Induces Maternal Tolerance to the Allogeneic Fetus in Abortion-Prone Matings

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Adoptive Transfer of Paternal Antigen-Hyporesponsive T Cells Induces Maternal Tolerance to the Allogeneic Fetus in Abortion-Prone Matings