Regulation of fetal tolerance by KIR+ regulatory CD8+ T cells in human pregnancy

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Abstract Immune responses during pregnancy need to be precisely regulated to protect the fetus from microbial infections and to maintain tolerance for the semi-allogeneic fetus. However, the mechanisms regulating fetal tolerance during pregnancy are not well understood. Recently we have identified KIR+CD8+ T cells as a previously unappreciated subset with regulatory functions in humans to suppress harmful self-reactivity. Therefore, we asked whether KIR+CD8+ T cells also play a role in inducing immune tolerance during pregnancy. We first observed an increased frequency of KIR+CD8+ T cells, but not CD4+ regulatory T cells (Tregs), in the peripheral blood of pregnant women at second trimester compared to age-matched nonpregnant females. Interestingly, those with a male fetus had an even higher level of KIR+CD8+ T cells than the ones with a female fetus. In vitro, we found that KIR+CD8+ T cells can suppress CD8+ T cells specific to H-Y antigens (encoded by the Y chromosome) only in mothers with a male fetus. Therefore, the higher induction of KIR+CD8+ T cells in mothers carrying a male fetus may suppress the additional allogenic immune responses triggered by the Y chromosome from the male fetus. Moreover, KIR+CD8+ T cells expand, lose memory features and gain cytotoxic capacity along gestation and their levels are maintained postpartum. In addition, we found the numbers of these suppressive CD8+ T cells correlated with pregnancy disorders, such as spontaneous abortion or pre-eclampsia. Taken together, our findings suggest an important role of KIR+CD8+ T cells in the maintenance of fetal tolerance by suppressing alloreactive fetus-specific T cells, therefore they may be useful as predictive biomarkers or drug targets for human pregnancy disorders. Supported by Howard Hughes Medical Institute.

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