Hyporesponsive fetus-specific T cell responses in multiparous human pregnancy

Pregnancy acts as both a tolerogenic and sensitizing event, inducing T cell hypofunction and humoral sensitization. Mouse studies reported that T cell hypofunction is a key mechanism in preserving fetal viability, but this phenomenon remains uncharacterized in humans. In this study, we developed an assay to specifically assess fetal-specific T cell tolerance in uncomplicated, full-term human pregnancies. The majority of maternal PBMCs stimulated with matured fetus-matched dendritic cells (CBDCs) exhibited low IFNγ responses that were significantly lower than third-party fetus-unmatched CBDCs. This hyporesponsiveness to matched CBDCs extended to the production of a range of Th1 and Th2 cytokines, and was not associated with increased immunoregulatory cytokines, IL-10 or IL-1RA. Unexpectedly, a small number of grand multiparous individuals displayed heightened IFNγ responses to fetus-matched CBDCs; these individuals also exhibited heightened Th1 and Th2 cytokine responses. Together, our study introduces a novel assay to measure fetal antigen-specific T cell responses that confirmed T cell hypofunction as an immunological mechanism enabling successful pregnancy in humans in addition to mouse. It also implicates alternative tolerance mechanisms that allow successful pregnancies to proceed even in the presence of fetus-specific T effector cell reactivity. These findings have implications for understanding immune dysregulation in pregnancy complications and for improving transplantation outcomes in multiparous women.