The fetus is antigenically distinct from the mother and therefore the maternal immune system must establish immunological tolerance towards the fetus to support pregnancy. Fetal-maternal tolerance is primarily mediated by a specialised subset of CD4+T cells known as regulatory T (Treg) cells. Absence or reduced function of Treg cells at embryo implantation causes infertility in mice and is implicated as a cause of reproductive disorders in women. The importance of adequate Treg cell responses during pregnancy is well recognised, however the factors which control the strength and quality of this response are not defined. The pregnancy hormone, progesterone (P4), is known to have potent immunosuppressive activity. To investigate the effects of P4 on Treg cells during pregnancy, mated female mice were administered low doses of the P4 antagonist, RU486, in the peri-implantation period. Flow cytometry analyses showed RU486 treatment resulted in decreased proportions of total Treg cells and increased proportions of IFNγ-producing Treg cells in the uterus-draining para-aortic lymph nodes. In vitro, P4 was found to repress IFNγ expression in Treg and T effector cells cultured under Th1-, Th17- and non-polarising conditions. Treg cells from mice with a null mutation in the nuclear progesterone receptor (nPR) also responded to P4 with attenuated IFNγ production, indicating the observed P4 effect was not mediated by nPR. Finally, using a membrane impermeable form of P4, we found Treg cells to be capable of binding P4 at the membrane. These findings suggest a non-classical mechanism for direct P4 action on Treg cells, potentially through membrane P4 receptors (mPRs). Collectively, our work demonstrates that P4 is a regulator of Treg cell abundance and cytokine production, which may be important in the establishment and maintenance of competent maternal tolerance during pregnancy.
11 Jul 2016 - 11 Jul 2016