In this study, we demonstrated the differences in CD4+
regulatory T cells in the peripheral blood of pregnant women according to gestational age, with or without PROM, and labor for the first time. Pregnancies with PROM during the third trimester showed a statistically lower population of CD4+
regulatory T cells in the blood than that of pregnancies without PROM. Inflammation has been implicated as a factor responsible for PROM. Many studies have focused on the detection of evidence of inflammation in both the maternal and fetal interface. 9,10
Regulatory T cells play a role in the generation of immunological tolerance to antigens and CD4+
regularoty T cells, among these regulatory T cells, have shown to have potent regulatory properties.11-13
Our results suggest that the regulatory T cells are involved in the maintenance of the decidua barrier at the fetal-maternal interface during late pregnancy. Due to the relative decrease in the percentage of CD4+
regulatory T cells in the peripheral blood, a woman could be susceptible to systemic inflammatory responses, possibly leading to a breakdown of the barrier. Consistent with our findings, a normal-term pregnancy has an increased percentage of CD4+
regularoty T cells in the decidua parietalis compared to the decidua basalis.5
However, the etiology of PROM is multifactorial. The present case-control study had a relatively small sample size and did not include pregnancies with preterm premature rupture of membranes. Therefore, the results should be interpreted with caution.
There are 2 arms of the immune system, the innate and the adaptive system, both of which have cellular and humoral components.14
During pregnancy, the maternal innate immune system is stimulated,15,16
and the adaptive response is either avoided or suppressed.17
This modulation might play an important role during implantation and in overall maternal defenses. Sasaki et al. demonstrated that CD4+
regulatory T cells are diminished in the blood and decidua in cases with spontaneous abortion compared to normal early pregnancy.3
Our study demonstrated that the percentage of CD4+
regulatory T cells increased in the blood samples from pregnant women compared to non-pregnant controls, and were the highest in the first trimester followed by the second and third trimesters although these differences were not statistically significant. In addition, CD4+
regulatory T cells have been reported to decrease in the maternal peripheral blood during the third trimester of pregnancy compared to the first and second trimester, however, with no differences detected between CD4+
regulatory T cells.4,18
In this study, we calculated the percentages of CD4+
regularoty T cells within the total number of lymphocytes. In contrast to our present results, a recent study showed that there was no significant change in the percentage of CD4+
regulatory T cells within the CD3+
cell fraction in the peripheral blood during early pregnancy (17 - 23 weeks gestation) compared to term pregnancy (37 - 42 weeks gestation).5
The differences in CD4+
T-cell subsets might be explained by different gestational ages at sampling time.
The process of decidual activation for the initiation of parturition stimulates an inflammatory reaction, which is an inevitable consequence of labor. During this inflammatory reaction, a number of cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1, 6, 8 and 12, are produced and these molecules activate granulocytes such as neutrophils and eosinophils.19
Initially, we hypothesized that the regulatory T cells might be diminished in women during labor, but, our results did not support this. Our study showed that the percentage of CD4+
regulatory T cells during the third trimester did not differ between women in labor and women not in labor. These findings might be due to activation of the innate immune system, which is an integral part of the immune response during labor, rather than the adaptive immune system regardless of regulatory T cells.
In conclusion, the increase in regulatory T cells during early pregnancy might be related to maternal tolerance during implantation period of the fetus. We identified for the first time the possibility that a decreased number of regulatory T cells might be one of the causes of PROM during the third trimester. Further study is needed to determine the relationship between PROM and regulatory T cells in a larger population of women under different conditions.