Elevated Soluble PD-L1 in Pregnant Women's Serum Suppresses the Immune Reaction

Abstract

Background: Programmed death-ligand 1 (PD-L1) is expressed not only on some cancer cells, but also on the outer surface of placental syncytiotrophoblasts, which is assumed to induce maternal immune tolerance to fetal tissue via programmed death-1 (PD-1) receptors on T cells. Recently, levels of soluble forms of PD-L1 (sPD-L1) were reported to be higher in the serum of pregnant women (PW) than in non-pregnant women (non-PW). However, there have been no reports of the functional significance of PW's serum containing high sPD-L1 levels. Therefore, the aim of the present study was to clarify the role of sPD-L1 in the sera of PW as an immunosuppressive molecule by in vitro assays. Methods: As a post-hoc analysis of our previous cohort study, 330 pairs of serum from PW during the third trimester and cord blood (CB) from paired offspring without major complications were examined. Serum levels of sPD-L1 and sPD-1 were measured by ELISA. On mixed lymphocyte culture (MLC), 3 H-thymidine uptakes in the presence of PW's, offspring's, or non-PW's serum were compared. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of PW's serum stimulated with PHA, and then cytokine levels were measured in supernatants by multiple cytokine analysis with or without anti-PD-L1blocking antibody. Results: The median sPD-L1 level was 8.3- and 6.9-fold higher in PW than in offspring and non-PW, respectively, whereas sPD-1 levels were lower in PW and offspring than in non-PW. On MLC, 3 H-thymidine uptake in the presence of autoantigen was strongly reduced by co-culture with serum of both PW and offspring, compared with serum of non-PW. In contrast, uptake in the presence of alloantigen was moderately inhibited by PW's serum, whereas it was less suppressed by offspring's serum, compared with non-PW's serum. In the culture of PBMCs, tumor necrosis factor-α, interferon gamma, interleukin (IL)-2, and IL-4 levels were significantly higher in the presence of anti-PD-L1 blocking antibody than in culture not treated with antibody (all P < 0.05 ) or culture treated with isotype control antibody (all P < 0.05 ). Conclusion: The levels of sPD-L1 are elevated in PW's serum, which may, at least in part, suppress maternal immunity.

Investigation of the PD-1 and PD-L1 Immune Checkpoint Molecules Throughout Healthy Human Pregnancy and in Nonpregnant Women

“…We found a decrease of PD-L1 expression on the surface of CD4+T and CD8+T cells in the 3rd trimester of pregnancy, which could affect the PD-1/PD-L1 pathway resulting in a Th1 predominance before and during delivery. Although, a recent publication revealed an increased soluble PD-L1 level in women from the 3rd trimester of pregnancy [38], which seems contradictory to our results. The source of circulating PD-L1 molecules could be either on placental trophoblast or from the surface of PD-L1 positive CD4+T and CD8+T cells, since it has not been defined in pregnancy yet [26,27,39,40].…”

Immune checkpoint molecules in pregnancy: Focus on regulatory T cells

“…Compared with sPD-L1, sPD-1 may enhance T-cell activation and antitumor response by blocking the interaction between PD-L1 and PD-1 via competitive inhibition [96]. Serum sPD-L1 level in pregnant women was higher than that of nonpregnant women and postpartum women, whereas sPD-1 levels were lower than that of nonpregnant women [97,98]. During pregnancy, placenta is considered the main source of sPD-L1 and elevated sPD-L1 at least partly attenuate maternal immune response, contributing to the induction of maternal immune tolerance toward the fetus (Fig 2) [97,98].…”

The prevalence of psychiatric symptoms of pregnant and non-pregnant women during the COVID-19 epidemic

“…In December 2019, unexplained pneumonia occurred in Wuhan, China and then became an epidemic. Now it is well-known as the 2019 coronavirus disease (COVID- 19) epidemic, which is spreading rapidly around the world, causing a high incidence and heavy economic burden 1,2 . On January 7, 2020, the novel coronavirus was identified as the pathogen of the epidemic by genome sequencing 3 .…”

“…Therefore, more attentions should be paid to the mental health of this special population. Moreover, pregnant women are at high risk of SARS-CoV-2 infection due to suppression of immune system functions 19 . During the COVID-19 epidemic, it is difficult for pregnant women to receive routine prenatal examinations or delivery, which may further increase the psychological burden of pregnant women.…”