Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

I t is conventional knowledge that a T helper type 2 (Th2)-type immunity is essential, dominant, and protective in the context of feto-maternal tolerance.[1][2][3][4] In mice, the expression of Th2-type cytokines, interleukin (IL)-4, IL-5, and IL-10, are reported at the feto-maternal interface (FMI).The Th2-type cytokine environment is maintained all throughout the gestation period, whereas interferon gamma (IFN-γ), an inflammatory T helper type 1 (Th1) cytokine, along with IL-11, tumor necrosis factor (TNF), and leukemia inhibitory factor (LIF) are, though essential, are transient and detectable in early pregnancy.[5] Thus, the simplistic concept of good-Th2 type and bad-Th1 type of response has been used to describe the phenomenon of feto-maternal tolerance.However, recurrent spontaneous abortions and preeclampsia are observed and reported in both Th1 and Th2 dominant immunity.Therefore, the Th1/Th2 paradigm does not adequately explain the mechanisms of tolerance at the FMI.[6] Further, identification of novel Th-type populations, namely T helper type 17 (Th17) and regulatory T cells (Tregs), adds more layers of complexity to the paradox of tolerance to the fetus.Both the Th17 and Treg populations have been shown to play a role in modulating the tolerance at the FMI.[7] This review aims to examine the crosstalk between Th17 and Tregs and the role of programmed death 1 (PD1)/PDL1 (ligand of PD1) pathway in induction and maintenance of tolerance at the FMI. Mechanisms of tolerance at the FMIA successful pregnancy is the result of maintenance of tolerance to the fetus by the maternal immune system, as well as protection from other harmful infections.A dysregulated maternal immunity is associated with complications in pregnancy resulting in fetal loss.The immune cells present in the uterus during the period of gestation are tightly regulated and a very fine balance exists between immunity and tolerance at the FMI.A number of different mechanisms are involved in the maintenance of feto-maternal tolerance and have been described and discussed in detail by various Special EditionTolerance of the fetus by the maternal immune system is regulated through various mechanisms involving the different immune cells, both in the periphery and locally at the feto-maternal interface.The maternal T lymphocytes are aware of the paternal fetal antigens and a state of dynamic T cell homeostasis is maintained in the uterus during gestation, which involves increase in antigen-specific regulatory T cell (Treg) proliferation, increase in apoptosis of antigen-specific effector T cells, and inhibition of excessive inflammation post successful implantation to ensure tolerance to the fetus.The Tregs play an important role in the maintenance of tolerance during gestation.Recently, the inflammatory T helper type 17 (Th17) cells are reported to have a role in loss of tolerance to the fetus.The interaction between costimulatory molecule programmed death 1 (PD1) and its ligand PDL1 is known to play a role in regulating both the Tregs and Th17 cells.Here we discuss how the PD1/PDL1 pathway affects these two T cell populations and its role in feto-maternal tolerance.