Pregnancy promotes tolerance to future offspring by programming selective dysfunction in long‐lived maternal T cells

Dysfunctional memory CD8+ T cells differentiate in the maternal repertoire which promotes pregnancy success, but can threaten subsequent tissue grafts. Fetal antigen available during pregnancy induces the proliferation of maternal T cells. It is unknown, however, whether these antigen‐activated T cells differentiate into long‐lived memory T cells that are capable of mediating rapid‐recall responses to tissue antigens. To test the hypothesis that pregnancy induces an alternative fate in fetal‐specific maternal T cells, we used a murine model to track longitudinally fetal‐specific T cells in pregnant and postpartum animals and test the response of these cells when challenged with the same antigen during sequential pregnancy or skin transplantation. Fetal‐specific CD8+ T cells were robustly primed during pregnancy but failed to acquire robust effector functions. These primed cells persisted long term in postpartum animals, frequently maintained a programmed death 1 (PD‐1)+ phenotype, and failed to expand or produce cytokines robustly in response to second pregnancy or skin transplantation. However, whereas there was no impact on second pregnancy as a result of the persistence of fetal‐primed memory CD8+ T cells in the mother, skin grafts bearing the same antigen were rejected more rapidly. Altogether, our data suggest that fetal antigen exposure during pregnancy induces the differentiation of long‐lived maternal CD8+ T cells with context‐dependent, selective effector dysfunction. This programmed effector dysfunction provides temporal and systemic restraint of maternal anti‐fetal alloreactivity to promote reproductive fitness efficiently, while preserving potentially protective effector T cell responses.