Helios-positive functional regulatory T cells are decreased in decidua of miscarriage cases with normal fetal chromosomal content

• Effector nTreg cells decreased in the decidua of subjects with miscarriage and normal embryo.
• Foxp3+ Teff cells increased in the decidua of subjects with miscarriage and a normal embryo.
• Decreased effector nTreg cells may constitute one of the risks of miscarriage.

Regulatory (Treg) T cells play essential roles in the maintenance of allogeneic pregnancy in mice and humans. Recent data show that Foxp3 expression occurs in both immuno-suppressive Treg and -nonsuppressive effector T (Teff) cells upon activation in humans. Samstein et al. (2012) reported that inducible Treg (iTreg) cells enforce maternal–fetal tolerance in placental mammals. Therefore, we should reanalyze which types of Treg cell play an important role in the maintenance of allogeneic pregnancy. In this study, we studied the frequencies of naïve Treg cells, effector Treg cells, Foxp3+ Teff cells, Helios+ naturally occurring Treg (nTreg) cells, and Helios− iTreg cells using flow cytometry. The frequencies of effector Treg cells and Foxp3+ Teff cells among CD4+Foxp3+ cells in the decidua of miscarriage cases with a normal embryo karyotype (n = 8) were significantly lower (P = 0.0105) and significantly higher (P = 0.0258) than those in normally progressing pregnancies (n = 11), respectively. However, these frequencies in miscarriages with an abnormal embryo karyotype (n = 15) were similar to those in normally progressing pregnancies. The frequencies of these cell populations in the three groups were unchanged in peripheral blood; on the other hand, most of the effector Treg cells in the decidua were Helios+ nTreg cells and these frequencies were significantly higher than those in peripheral blood, while those among effector Treg and naïve Treg cells in the decidua and peripheral blood were similar among the three groups. These data suggest that decreased Helios+ effector nTreg might play an important role in the maintenance of pregnancy in humans.