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

Sci Signal. 2017 Sep 26;10(498):eaah4323. doi: 10.1126/scisignal.aah4323.

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.

MeSH terms

  • Abortion, Habitual / diagnosis
  • Abortion, Habitual / immunology*
  • Animals
  • Biomarkers / blood
  • Disease Models, Animal
  • Female
  • Galectins / metabolism*
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Hepatitis A Virus Cellular Receptor 2 / metabolism*
  • Humans
  • Immune Tolerance / immunology*
  • Killer Cells, Natural / immunology*
  • Male
  • Maternal-Fetal Exchange / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred CBA
  • Mice, Inbred DBA
  • Pregnancy

Substances

  • Biomarkers
  • Galectins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • LGALS9 protein, mouse
  • galectin 9, mouse