Research ArticleImmunology

Tim-3 signaling in peripheral NK cells promotes maternal-fetal immune tolerance and alleviates pregnancy loss

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Sci. Signal.  26 Sep 2017:
Vol. 10, Issue 498, eaah4323
DOI: 10.1126/scisignal.aah4323

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Mediating maternal-fetal tolerance

Many cases of recurrent miscarriage are due to a breakdown in immune tolerance between the mother and the fetus. Determining the underlying mechanism may aid in the identification of biomarkers for recurrent miscarriage and suggest possible therapies. Li et al. found that the abundance of the type I membrane receptor Tim-3 was increased on the surface of peripheral natural killer (pNK) cells in the first trimester of pregnancy. These cells produced anti-inflammatory cytokines and induced the generation of immunosuppressive cells. In contrast to pNK cells from donors with normal pregnancies, those from recurrent miscarriage patients had decreased Tim-3 abundance and were defective in immunosuppression. Experiments with abortion-prone mice showed that Tim-3+ pNK cells, but not Tim-3 pNK cells, protected against fetal loss, suggesting that Tim-3+ pNK cells promote maternal-fetal immune tolerance.

Abstract

Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)–signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3+ pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (Tregs) in a transforming growth factor–β1 (TGF-β1)–dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3+ pNK cells was impaired. Compared to Tim-3+ pNK cells from donors with normal pregnancies, RM patient Tim-3+ pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3+ pNK cells, but not Tim-3 pNK cells, reduced fetal loss in abortion-prone and NK cell–deficient mice. Together, our findings reveal a critical role for Tim-3–Gal-9 signaling–mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.

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