The Link between the PDL1 Costimulatory Pathway and Th17 in Fetomaternal Tolerance

Abstract

Fetomaternal tolerance has been shown to depend both on regulatory T cells (Tregs) and negative signals from the PD1-PDL1 costimulatory pathway. More recently, IL-17-producing T cells (Th17) have been recognized as a barrier in inducing tolerance in transplantation. Herein we investigate the mechanisms of PDL1-mediated regulation of fetomaternal tolerance using an alloantigen-specific CD4+ TCR transgenic mouse model system (ABM-tg mouse). PDL1 blockade led to an increase in embryo resorption and a reduction in litter size. This was associated with a decrease in Tregs, leading to a lower Treg/Teff ratio. Moreover, PDL1 blockade inhibited antigen-specific alloreactive T cell apoptosis, induced Tregs' apoptosis and a shift towards higher frequency of Th17 cells, breaking fetomaternal tolerance. These Th17 cells arose predominantly from CD4+Foxp3− cells, rather than from Tregs' conversion. Locally in the placenta, similar decrease in regulatory and apoptotic markers was observed by RT-PCR. Neutralization of IL-17 abrogated the anti PDL1 effect on fetal survival rate and restored Tregs' number. Finally, the adoptive transfer of Tregs was also able to improve fetal survival in the setting of PDL1 blockade. This is the first report utilizing an alloantigen-specific model that establishes a link between PDL1, Th17 cells and fetomaternal tolerance.

Granulocyte-Colony Stimulating Factor as Treatment Option in Patients with Recurrent Miscarriage

“…Treg cells seem to predict miscarriage in pregnant women with a history of failure (Winger et al 2009). T cell subsets like Th17 promote a pro-inflammatory immune reaction and are negatively controlled by Tregs (D'Addio et al 2011). In the peripheral blood of patients with idiopathic RM, the expression of Th17-positive cells seems to be significantly increased when compared to women with healthy pregnancies (Wang et al 2010).…”

Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal–fetal interface

“…T cells are also present in the decidua, where they can recognize alloantigens and become inflammatory. Previous reports have shown that T H 17 cells represent a barrier to the induction of tolerance in transplantation and pregnancy (17,46,47). To investigate the presence of T H 17 cells, we first assayed the IL-17-producing T cells present in the decidua during different phases of pregnancy.…”

“…For example, T H 2 cytokine polarization (6)(7)(8)(9), the expression of the Fas ligand on trophoblast cells (10), and the inhibition of complement activation (11) are crucial for ensuring tolerance at the maternal-fetal interface. In addition, a delicate balance exists between inhibitory (PD-L1, Stat3, and TGF-β1) and stimulatory (CD80 and CD86) signals during the establishment of immune privilege (12)(13)(14)(15)(16)(17)(18). Furthermore, studies have shown that galectin-1 (19) and indoleamine 2,3-dioxygenase (20) play pivotal roles in maternal-fetal tolerance.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…However, they did not observe a conversion of Tregs to Th17 phenotype following anti-PDL1 treatment; rather, they saw an increase in IL-17 producing CD4 + Foxp3 − − cells and also a decrease in conversion of CD4 + Foxp3 − − cells into CD4 + Foxp3 + cell type. [79] Figure 1 illustrates the interaction between Treg and Th17 cells.…”

“…The PD1/PDL1 pathway plays an important role in this mix, as it directly affects the suppressive properties of the Treg population [46] as well as abrogates the protective effects of Treg treatment. [42] Blockade of PD1/ PDL1 pathway also prevents the conversion of naïve Th cells to a Treg phenotype, [79] thereby creating a bias toward an inflammatory environment that is conducive for the survival and expansion of both Th1 and Th17 types of cell populations. Th17 cells are involved in fetal loss, as discussed earlier in this article, by creating an excessive inflammatory microenvironment at the FMI.…”