Regulatory KIR⁺CD8⁺ T cells are elevated during human pregnancy

During pregnancy, immune responses must balance protection from infections with tolerance of the semiallogeneic fetus. However, the mechanisms regulating maternal-fetal tolerance remain poorly understood. Recently, we identified CD8⁺ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) as a regulatory subset important for suppressing self-reactivity in human autoimmune and infectious diseases. To better understand what other roles these cells might play, we asked whether they are active during pregnancy. We first observed an increased frequency of KIR⁺CD8⁺ T cells in the peripheral blood of pregnant people in the second trimester, especially in those carrying a male fetus. In vitro, KIR⁺CD8⁺ T cells inhibited the alloreactive responses of maternal T cells against irradiated cord blood cells and selectively suppressed CD8⁺ T cells targeting male-specific proteins in mothers with male pregnancies. Therefore, the higher induction of KIR⁺CD8⁺ T cells in mothers carrying a male fetus may help suppress additional allogeneic responses triggered by male-specific alloantigens. Longitudinal analysis showed that KIR⁺CD8⁺ T cells undergo expansion and differentiate into functional cytotoxic cells during pregnancy. Single-cell RNA sequencing of decidual CD8⁺ T cells from early pregnancy revealed elevated numbers and increased expression of activation markers in KIR⁺CD8⁺ T cells at the maternal-fetal interface. In addition, a higher frequency of KIR⁺CD8⁺ T cells was associated with spontaneous abortion and preeclampsia. Together, our findings suggest that KIR⁺CD8⁺ T cells may contribute to maternal tolerance by modulating fetal-specific alloreactive T cell responses. They may also be useful as candidate biomarkers or therapeutic targets for human pregnancy disorders.