Pregnancy imprints regulatory memory that sustains anergy to fetal antigen

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Abstract
Successful pregnancy requires immune tolerance against paternal antigens expressed by the fetus; here pregnancy is shown to stimulate the selective accumulation of maternal immune-suppressive regulatory T cells with fetal specificity that are retained post-partum, which may explain the protective benefits of prior pregnancy against pre-eclampsia and other complications in subsequent pregnancy. Successful pregnancy requires the development of effective tolerance mechanisms for fetus antigens inherited from the father, which evoke an immune response because they are considered ‘non-self’ by the maternal immune system. Jared Rowe et al. show here that this is accomplished by the generation of maternal regulatory T cells with specificity for fetal antigens. Fetal-specific regulatory T cells re-accumulate with accelerated kinetics during secondary pregnancy and may explain why partner-specific secondary pregnancies show reduced rates of pre-eclampsia and other complications. Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3+ regulatory T cells (Treg cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss1,2. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal Treg expansion3,4,5. Importantly, however, the antigen specificity and cellular origin of maternal Treg cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3+ CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells6. Interestingly, after delivery, fetal-specific Treg cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of Treg cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3+ cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3+ cells each contribute to Treg expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3+ cell ablation. Thus, pregnancy imprints FOXP3+ CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting Treg cell memory.

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