The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy

Songcun Wang,Fengrun Sun,Mengdie Li,Dajin Li,Mingyan Wang,Chunqin Chen,Min Yu,Xingxing Zang,Meirong Du,Jinfeng Qian

doi:10.1038/s41419-019-1642-x

Abstract

Maternal decidual CD8+ T (dCD8+ T) cells must integrate the antithetical demands of maternal–fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8+ T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8+ T cells during pregnancy and found the higher frequency of Tim-3+CTLA-4+dCD8+ T cells in response to trophoblasts. This Tim-3+CTLA-4+dCD8+ T cells subset showed an active status and produced more anti-inflammatory cytokines. Furthermore, the decreased number and altered function of Tim-3+CTLA-4+dCD8+ T cells correlated to miscarriage. Combined blocking Tim-3 and CTLA-4 pathways were highly effective in inhibiting the production of anti-inflammatory cytokines and were detrimental to the maintenance of pregnancy. Together, these findings supported that Tim-3 and CTLA-4 pathways might play positive roles in the establishment and/or maintenance of maternal–fetal tolerance so to promote the maintenance of normal pregnancy. So the reproductive safety must be considered, especially when anti-Tim-3/CTLA-4 antibody (and other immune checkpoint inhibitors) are used in pregnancy.

Highlights

During a successful pregnancy in placental mammals, the balance between immune tolerance allowing allogeneic fetal trophoblasts (Tros) to invade maternal tissues and immune defense against a variety of pathogens is required to be established
We first compared the expression levels of T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on CD8+ T cells from paired decidua and peripheral blood freshly isolated from clinically normal first-trimester pregnancies
Tim-3 and CTLA-4 were expressed on significantly higher proportions of Decidual CD8+ T (dCD8+ T) cells than in peripheral CD8+T cells, as the Tim-3+CTLA4+ cells comprised about 14% of dCD8+ T cells, while only 1% of pCD8+ T cells

Summary

Introduction

During a successful pregnancy in placental mammals, the balance between immune tolerance allowing allogeneic fetal trophoblasts (Tros) to invade maternal tissues and immune defense against a variety of pathogens is required to be established Disruption of this immune balance is believed to be associated with a lot of. High-protein expression of coinhibitory molecules was observed on effector-memory dCD8+ T cells[6,7] These co-inhibitory molecules, including T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have been implicated to identify dysfunctional T cells, as progressive increase in the diversity and amount of coinhibitory molecules expressed on T cells leads to the dysfunction of T cells[8,9]. Blockade of these inhibitory receptors to improve T-cell responses is considered as a novel strategy for the treatment of chronic infection and some tumors[10,11]

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