CCR8+ decidual regulatory T cells maintain maternal-fetal immune tolerance during early pregnancy.

Regulatory T (Treg) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. Treg cell population heterogeneity and tissue-specific functions in the human decidua remain largely unknown. Here, using single-cell transcriptomic and T cell receptor sequencing of human CD4+ T cells from first-trimester deciduae and matched peripheral blood of pregnant women, we identified a highly activated, immunosuppressive CCR8+ Treg cell subset specifically enriched in the decidua (dTreg cells). CCR8+ dTreg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8+ dTreg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8+ Treg cells rescued fetal loss in abortion-prone mice. The CCR8 ligand CCL1 was mainly produced by decidual CD49a+ natural killer cells and was significantly decreased in patients with RPL. Our data demonstrate that CCR8+ dTreg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.