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

Regulatory T (T_reg) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. T_reg 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⁺ T_reg cell subset specifically enriched in the decidua (dT_reg cells). CCR8⁺ dT_reg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8⁺ dT_reg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8⁺ T_reg 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⁺ dT_reg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.