Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions

Abstract

Leukemia inhibitory factor is essential for embryo implantation, and a shift from type 1 T-helper to type 2 T-helper response at the fetal-maternal interface may contribute to successful pregnancy. We show that LIF production is associated with type 2 T-helper cells, is upregulated by IL-4 and progesterone and is downregulated by IL-12, IFN-gamma and IFN-alpha. We also show a decreased production of LIF, IL-4 and IL-10 by decidual T cells of women with unexplained recurrent abortions in comparison with that of women with normal gestation. The defective production of LIF and/or type 2 T-helper cytokines may contribute to the development of unexplained recurrent abortions.

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

“…8 Decidual CD4 1 and CD8 1 T cells from miscarriages are defective in IL-4 and IL-10 production in comparison with decidual T cells from normal pregnancy. 9 Consistent with this, the expression of a chemoattractant receptor homologous molecule on Th2 cells (a marker of IL-4-producing cells) in CD4 1 and CD8 1 T cells has been reported at the site of implantation in successful pregnancy. 10 The commitment to Th1 or Th2 phenotypes can be brought about by multiple mechanisms, including the differential expression of distinct cytokine genes and transcriptional factors.…”

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

“…The "Th1/Th2 paradigm" proposes that Th2-type cytokines such as IL-4 and IL-10 may favor the maintenance of mammalian pregnancy [6,[10][11][12], whereas the excessive production of Th1 cytokines (IL-2, IFN-c, TNF-a) would mediate the rejection of the fetus at the feto-maternal interface [10,[13][14][15][16][17]. Thus, we wondered whether the protective effects observed after transfer of pregnancy-induced Treg were related to a down-regulation of "abortive" cytokines (Th1) and/or to an up-regulation of pregnancy-protective (Th2) cytokines.…”

“…Th1/Th2 cytokine balance with Th2 predominance has been seen as a very important mechanism determining the survival of the fetus in the maternal uterus [6][7][8][9][10][11][12][13][14][15][16][17]. However, mice genetically deficient for IL-4 and IL-10 do not show disturbed pregnancy [18], suggesting that Th2 cells are not essential for normal pregnancy and alloreactive Th1 cells must be differently regulated, as already proposed [19][20][21].…”

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

“…3,4 Studies in women have suggested that Th1-type immunity to trophoblast antigens 5,6 and defective Th2 cytokine production by decidual T cells are associated with RPL. 7 Th1-type immunity may contribute to reproductive failure, since Th1 cytokines such as interferon-gamma (IFN-␥) and tumor necrosis factor-alpha (TNF-␣) have been demonstrated to disrupt a number of reproductive process in vitro. 8,9 Potential molecular and genetic mechanism(s) underlying these phenomena remain unknown.…”

“…Altered IL-1␤ production in the decidua may explain the defective production of Th2 cytokines by decidual T cells recently reported in women with RPL. 7 Altered IL-1␤ production may also contribute to pregnancy by directly affecting trophoblast growth and invasion during early pregnancy. These mechanisms are distinct from those in other diseases associated with over-production and pro-inflammatory effects of IL-1.…”