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

S-C Wang,D-J Li,M-M Yuan,H-L Piao,Y Tao,Y-H Li,D Zhang,Y Wang,X-W Hong,Y-Y Xu,M-R Du

doi:10.1038/cddis.2015.112

Abstract

CD8+ 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+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ 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 in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ 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+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ 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+ T-cell function and maintaining normal pregnancy.

Highlights

Type cytokine interleukin (IL)-10 or blockade of the Th1-type cytokine tumor necrosis factor (TNF)-α is known to prevent pregnancy loss induced by lipopolysaccharide.[3,4]
To investigate the potential role of T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) in CD8+ T-cell function during pregnancy, we first examined their expressions on CD8+ T cells and found that cells co-expressing Tim-3 and PD-1 comprise about 15% of d CD8+ T cells and less than 6% of peripheral CD8+ T cells in early pregnancy (Figure 1a)
Tim-3−PD-1−CD8+ T cells accounted for over 55% of peripheral blood mononuclear cells (PBMCs) and around 40% of decidual immune cells (DICs). These results demonstrate that Tim-3+PD-1+CD8+ T cells are preferentially distributed in decidua

Summary

Introduction

Type cytokine interleukin (IL)-10 or blockade of the Th1-type cytokine tumor necrosis factor (TNF)-α is known to prevent pregnancy loss induced by lipopolysaccharide.[3,4]. HLA-C and HLA-G, highly expressed on EVT cells,[6] can elicit a direct cytotoxic response by CD8+ T cells during hematopoietic stem cell and allogeneic organ transplantation.[7,8] whether suppressor or regulatory CD8+ T cells are present at the maternal–fetal interface, and how they function to maintain normal pregnancy, remain to be explored. It has been shown that exhausted T cells express up to seven different inhibitory molecules,[9] including PD-1 and Tim-3. PD-1 has been identified as a marker for dysfunctional T cells, and blockade of PD-1 signals has been shown to revert the dysfunctional state of exhausted CD8+ T cells in most cases.[10,11] Tim-3 has been associated with CD8+. T-cell exhaustion as Tim-3 blockade restores proliferation and cytokine production.[12,13] Tim-3 and PD-1 co-expression on T cells characterizes the most severely exhausted CD8+ T-cell subset, and combined blockade of Tim-3 and PD-1 restores the function of exhausted CD8+ T cells.[14,15,16] much less is known about the functional regulation of Tim-3 and PD-1 on CD8+ T cells during pregnancy

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Results

Conclusion