Maternal B Cell-Intrinsic MyD88 Signaling Mediates LPS-Driven Intrauterine Fetal Death.

Immunological networks balance tolerance towards paternal alloantigens during pregnancy with normal immune response to pathogens. Subclinical infections can impact this balance and lead to preterm birth or even intrauterine fetal death (IUFD). We recently showed that loss of maternal B cells renders murine fetuses susceptible to IUFD after LPS exposure. Since the signaling pathway involved in this B-cell mediated response remains unclear, we aimed to understand the participation of MyD88 in this response using B-cell-specific MyD88-deficient (BMyD88-/-) mice. B cells isolated from wild-type (WT), BMyD88-/-, CD19-/- and MyD88-/- dams on gestational day (gd) 10 responded differently to LPS concerning cytokine secretion. In vivo LPS challenge on gd 10 provoked IUFD in CD19-/- mothers with functional MyD88, while fetuses from BMyD88-/- and MyD88-/- mice were protected. These outcomes were associated with altered cytokine levels in the maternal serum and changes in CD4+ T-cell responses. Overall, the loss of MyD88 signaling in maternal B cells prevents the activation of cytokine release that leads to IUFD. Thus, while MyD88 signaling in maternal B cells protects the mother from infection, it ultimately kills the fetus. Understanding the cellular mechanisms underlying infection-driven pregnancy complications is the first step to designing powerful therapeutic strategies in the future.

IL-10 producing B cells rescue mouse fetuses from inflammation-driven fetal death and are able to modulate T cell immune responses.

Understanding the mechanisms leading to fetal death following maternal subclinical infections is crucial to develop new therapeutic strategies. Here we addressed the relevance of IL-10 secreting B cells (B10) in the maintenance of the immune balance during gestation. µMT females lacking mature B cells presented normal pregnancies, although their fetuses were smaller and their Treg pool did not expand as in B cell sufficient controls. Pregnant µMT females were more susceptible to LPS despite having less Treg; their fetuses died at doses compatible with pregnancy in WT animals. Adoptive transfer of IL-10 negative B effector cells or B cells from IL-10 deficient mice did not modify this outcome. The transfer of B10 cells or application of recombinant murine IL-10 reduced the fetal loss, associated with a normalization of Treg numbers and cytokine modulation at the feto-maternal interface. B cell-derived IL-10 suppressed the production of IL-17A and IL-6 by T cells and promoted the conversion of naïve cells into Treg. B10 cells are required to restore the immune balance at the feto-maternal interface when perturbed by inflammatory signals. Our data position B cells in a central role in the maintenance of the balance between immunity and tolerance during pregnancy.