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Pregnancy imprints regulatory memory that sustains anergy to fetal antigen

Abstract

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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Figure 1: Accumulation of maternal CD4 and FOXP3 + T reg cells with fetal specificity during gestation.
Figure 2: Accelerated expansion of maternal T reg cells with fetal specificity during secondary pregnancy.
Figure 3: The post-partum environment maintains anergy for maternal CD4 cells with pre-existing fetal specificity.
Figure 4: Maternal post-partum T reg cells mitigate IFN-γ responsiveness and mediate resiliency to fetal resorption in secondary pregnancy.

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Acknowledgements

We thank M. Jenkins for providing 2W1S-expressing mice, and A. Rudensky for providing Foxp3DTR mice. This research was supported by NIH-NIAID awards R01AI087830 and R01AI100934 (S.S.W.), and NIH-NIDDK award F30DK084674 (J.H.R.). S.S.W. holds an Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund.

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J.H.R., J.M.E., L.X. and S.S.W. designed and performed the experiments, and wrote the paper.

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Correspondence to Sing Sing Way.

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The authors declare no competing financial interests.

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Rowe, J., Ertelt, J., Xin, L. et al. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–106 (2012). https://doi.org/10.1038/nature11462

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