PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy

<jats:title>Abstract</jats:title> <jats:p> CD8 <jats:sup>+</jats:sup> T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3 <jats:sup>+</jats:sup> PD-1 <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8 <jats:sup>+</jats:sup> T cells upregulated PD-1 <jats:sup>+</jats:sup> and/or Tim-3 <jats:sup>+</jats:sup> immune cells. Furthermore, the population of CD8 <jats:sup>+</jats:sup> T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased <jats:italic>in vitro</jats:italic> proliferation and Th2-type cytokine production while increased trophoblast killing and IFN- <jats:italic>γ</jats:italic> producing capacities of CD8 <jats:sup>+</jats:sup> T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8 <jats:sup>+</jats:sup> T-cell dysfunction. Importantly, the number and function of Tim-3 <jats:sup>+</jats:sup> PD-1 <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8 <jats:sup>+</jats:sup> T-cell function and maintaining normal pregnancy. </jats:p>