Altered T‐cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities

Abstract

Recurrent pregnancy loss (RPL) is a multifactorial disorder of women in reproductive age, which in some cases is caused by immunologic abnormalities. In this study, we aimed to evaluate cellular and molecular components of the immune system like different T-cell subsets and their regulating microRNAs (miRNAs) in RPL women and control group. Fifty RPL and 50 healthy subjects were recruited. Subsets of T cells, including regulatory T (Treg) cells, helper T (Th) 17 cells, exhausted T cells, exhausted Treg cells were evaluated by flow cytometry. Transcription factors of T cells and related miRNA profile were quantified using real-time polymerase chain reaction (RT-PCR). Assessment showed that Treg and exhausted T cells, were decreased in RPL patients (p = 0.009 and 0.02, respectively), while an increase was observed in Th17 and exhausted Treg frequency ( p = 0.013 and 0.0037, respectively). Messenger RNA expression level of T-bet and IRF4 was upregulated in RPL patients ( p = 0.011 and 0.0001, respectively), while Th2- and Treg-related transcription factors, GATA3 and GITR, were downregulated in these patients compared with the healthy subjects ( p = 0.0008 and <0.000, respectively). Treg-associated miRNAs, the miR-106b-25-93 cluster, showed a higher rate in RPL patients ( P = 0.007, 0.001, and 0.029, respectively), however, we observed no significant difference in the expression level of Th17-associated miRNA, mir-326. According to the results, we concluded that unbalanced immune responses and deregulated function of T-cell subsets may lead to reproduction-related failure like a miscarriage. Therefore, evaluation of immune cells and related miRNA profile may serve as prognostic biomarker for the treatment of RPL patients.

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“…As CD4 + CD25 + Treg was responsible for the immune suppression of TME, the negative regulation effect of Sfn on these cells was supposed to exert beneficial effects on the restoration of the function of effector T cells and DC cells to fully induce immune response. 37 …”

The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

“…The role of Tregs in connection with the uterine (u)NK cells in the endometrium of infertile women has been thoroughly described in a recent review by Kofod et al (196). Reduced numbers of Tregs, and increased number of CD8 + T cells and Th17 cells, have also been associated with pregnancy complications such as pre-eclampsia (PE) and RPL (191, 192, 197). In mice, depletion of Tregs using anti-CD25 monoclonal antibodies at the time of implantation resulted in poor implantation and fetal reabsorption in allogeneic, but not in syngeneic pregnancies.…”

“…The function of Tregs during pregnancy mirror those occurring in the tumor microenvironment, in which Tregs regulate other immune cells present in the maternal-fetal interphase (Figures 1, 3). Tregs limit the effect of allogen-specific Teff cells by the expression of CD25, CTLA-4, and the PD-L1 pathway and the secretion of IL-10 and TGF-β that induce apoptosis and suppress cytotoxicity in recipient cells (171, 173, 176, 197). PD-L1 expression by Treg cells has been found to inhibit proliferation of CD4 + CD25 − T cells and suppress expression of the pro-inflammatory cytokines IFN-γ and TNF-α (224).…”

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