The Effect of TGF-β on Treg Cells in Adverse Pregnancy Outcome upon Toxoplasma gondii Infection

Abstract

Toxoplasma gondii (T. gondii) is a ubiquitous intracellular protozoan parasite that causes adverse pregnancy outcomes. Its infection downregulates the Treg cell population and TGF-β level, which may contribute to adverse pregnancy outcomes. TGF-β plays a critical role in Treg cell development, but whether TGF-β treatment can affect the number and function of Treg cells and hence alleviate adverse pregnancy outcomes caused by T. gondii infection remains elusive. In this study, T. gondii-infected pregnant mice were treated with TGF-β or TGF-β-neutralizing antibody. The pregnancy outcomes were observed on gestational day 14. The numbers of Treg cells and pSmad3, programmed death 1 (PD-1), and Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) expression of Treg cells were analyzed by flow cytometry. Histological changes were assessed using HE staining, while IL-10 and TNF-α levels were measured using ELISA. The results indicated that TGF-β treatment improved the T. gondii-induced adverse pregnancy outcomes, with alleviation of hemorrhage, restoration of uterine spiral arteries of the placenta, and increased Treg cell numbers; meanwhile, TGF-β neutralization resulted in more serious adverse pregnancy outcomes, with serious hemorrhage, more dilated uterine spiral arteries, and decreased Treg cell numbers. pSmad3 expression in CD4+ cells and CTLA-4 and PD-1 levels on Treg cells were upregulated by TGF-β treatment, but downregulated by TGF-β neutralization. The ratio of IL-10/TNF-α also increased after TGF-β treatment, but decreased after TGF-β neutralization. Our data indicate that TGF-β treatment could improve adverse pregnancy outcomes caused by T. gondii infection by upregulating Treg cell differentiation and function via the TGF-β/Smad3 signaling pathway, but not the proliferation of Treg cells.

HO‐1 regulates the function of Treg: Association with the immune intolerance in vitiligo

“…Recently, it is reported that Tregs are suppressed in vitiligo not only on their amounts but also on their function. The polymorphisms of several immunosuppressive genes expressed in Tregs including transcription factor Forkhead box P3 (Foxp3), interleukin‐10 (IL‐10) and transforming growth factor β (TGF‐β) are associated with susceptibility to vitiligo. Moreover, the function of Tregs has been shown impaired in vitiligo patients, with weaker suppressive effect of Tregs on autologous CD8 + T cells and decreased expression level of Foxp3 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) that induces the anergy of effector T cells .…”

A Proinflammatory Immune Response Might Determine Toxoplasma gondii Vertical Transmission and Severity of Clinical Features in Congenitally Infected Newborns

“…The immune response has been proposed as a critical factor involved in the control of the parasite T. gondii in individuals with acquired toxoplasmosis (11,(15)(16)(17)(18)(19)(24)(25)(26). We previously reported that T. gondii vertical transmission might be related to those cases positive to proinflammatory cytokines such as IFN-γ and negative to the immunoregulatory cytokine TGFβ (19).…”

Cellular immunopathogenesis in primary Toxoplasma gondii infection during pregnancy

“…However, abnormal pregnancy in T. gondii ‐infected mice could be improved by increasing expression of cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) and programmed death 1 (PD‐1) on Treg cells . Using a mouse model, a different group reported that TGF‐β treatment improved the abnormal pregnancy caused by T. gondii infection by increasing Treg differentiation and function via the TGF‐β/Smad3 signalling pathway …”