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 (Tregs), because even transient partial ablation triggers fetal-specific effector T cell activation and pregnancy loss1,2. In turn, many idiopathic pregnancy complications proposed to stem from disrupted fetal tolerance are associated with blunted maternal Treg expansion3–5. Importantly however, the antigen-specificity and cellular origin of maternal Tregs that accumulate during gestation remain undefined. Here we show 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 Tregs persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of Tregs during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific Foxp3+ cells retained from prior pregnancy, while 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 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 regulatory T cell memory.

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…These cells are peripherally induced, as their differentiation depends on both paternal antigens and the conserved noncoding sequence-1 (CNS1) enhancer element that contains a Smad-binding site at the Foxp3 locus (Zheng et al 2010;Rowe et al 2012;Samstein et al 2012). Female mice that lack CNS1 have higher rates of embryo resorption when mated with allogeneic, but not syngeneic, males, confirming that pTreg cells modulate maternal immune responses to paternal alloantigens during pregnancy (Samstein et al 2012).…”

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

“…Maternal Tregs have been studied in the context of healthy and pathologic pregnancies 2, 4, 5, 35. In contrast, very little is known about a potential role of fetal Tregs in pregnancy disorders.…”

“…To cope with these significant antigenic differences, mechanisms of immune tolerance are invoked during pregnancy 2, 4, 5. Among these are the actions of the powerful T regulatory (Treg) cell that has the ability to negatively regulate major portions of the cellular immune system 6.…”

“…Among these are the actions of the powerful T regulatory (Treg) cell that has the ability to negatively regulate major portions of the cellular immune system 6. During pregnancy, the mother develops Treg specificity for fetal antigens and, similarly, the fetus develops Tregs with specificity for non‐inherited maternal antigens 1, 2, 3. During preeclampsia, there is significant evidence demonstrating markers of maternal immune activation as part of the disease 7.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…All of the above and a more detailed discussion on the role of Tregs in murine and human pregnancies are discussed in the review by Teles et al [67] The role of Tregs in maintaining tolerance at the periphery and also locally at the FMI during gestation is extensively studied and is well established. [68,69] The recent understanding in Treg plasticity and their conversion to Th17-type cells is important in the context of feto-maternal tolerance and needs to be addressed as more reports of Th17 cell involvement in fetal loss emerge.…”