Innate immune defenses at the maternal-fetal interface

Abstract

The human maternal-fetal interface is an immunologically complex environment that must balance the divergent demands of tolerance towards the developing fetus with anti-pathogen defense. The innate immune responses at the maternal-fetal interface that function in anti-microbial defense have been understudied to-date and how 'TORCH' pathogens evade maternal innate immunity to infect the fetus remains poorly understood. Herein, we discuss how newly described decidual innate lymphoid cells and maternal placenta-associated macrophage subsets may be involved in anti-pathogen defense. Moreover, we outline recent advances in our understanding of how placental trophoblasts and fetal-derived macrophages (Hofbauer cells) function in anti-microbial defense. In summary, we highlight current gaps in knowledge and describe novel experimental models of the human decidua and placenta that are poised to advance our knowledge of innate immune defenses at the maternal-fetal interface.

Figure 1.. Overview of the maternal-fetal interface.

The maternal-fetal interface is comprised of the maternal-derived decidua and fetal-derived placental villi. Maternal-derived innate immune cells include decidual natural killer (dNK) cells, non-NK decidual innate lymphoid (dILCs), placenta-associated maternal macrophages and monocytes (PAMMs), and decidual dendritic cells (dDCs). In early gestation, the fetal placental villi become bathed in maternal blood that is delivered by the spiral arteries to form the intervillous space, which contains maternal immune cells, nutrients, antigens, antibodies, and bloodborne pathogens. The placenta contains different trophoblast populations with diverse innate immune functions including invading extravillous trophoblasts (EVTs), which remodel the spiral arteries, anchor the placental villi to the maternal decidua, and promote tolerance, as well as, cytotrophoblasts (CTB). While CTB are present in a contiguous layer surrounding the placental-villi in early gestation, these trophoblasts fuse to form the multi-nucleated syncytiotrophoblast (STB) layer later in gestation. The only fetal-derived immune cells in the placenta are primitive macrophages termed Hofbauer cells (HBCs), which are abundant throughout the placental villi from early gestation and throughout pregnancy. Figure was generated using Biorender.

Figure 2.. Decidual innate immune defenses.

Though innate immune cells in the maternal decidua are primarily anti-inflammatory and immunotolerant, there is emerging evidence that dNK and PAMM cell subsets are highly heterogenous and may play a role in anti-microbial innate immune defense. Although dNK cells have low cytotoxic potential, they also contain granules of antimicrobial peptides (e.g., perforin, granzyme, and granulysin) and can use nanotubules to transfer granulysin to EVTs to kill intracellular pathogens. Whether other anti-microbial mechanisms (e.g., Fc receptor effector functions) are employed by dNKs remains unclear and should be explored. Whether EVTs function independently in anti-microbial responses is also unknown, though they express pathogen recognition receptors (PRRs) including toll-like receptors (TLRs) and nod-like receptors (NLRs) that can facilitate pathogen detection. PAMM subsets are diverse and while some are biased towards an anti-inflammatory/M2 phenotype that has classically been ascribed to maternal decidual macrophages, others have more clear pro-inflammatory/M1-like functions. For instance, PAMMs can release pro-inflammatory cytokines following TLR stimulation and present antigen through MHC class II receptors; however, whether decidual PAMMs phagocytose pathogens directly or mediate Fc receptor effector functions such as antibody-dependent cellular phagocytosis is less clear and should be investigated. Figure was generated using Biorender.

Figure 3.. Placental-villi innate immune defenses.

Placental villi have robust anti-microbial defense mechanisms to prevent congenital infections; however, certain TORCH pathogens are able to subvert these innate immune defenses to infect the developing fetus. The multi-nucleated STB layer is a key physical defense against pathogens that also constitutively secretes type III interferons, microRNAs, and antimicrobial peptides. Moreover, the STB contains numerous TLRs and NLRs for pathogen detection that initiate rapid innate immune signaling. The STB also facilitates passive transplacental antibody transfer, though this may inadvertently also facilitate immune complex transfer, allowing certain viruses to bypass STB defenses. Recently described placental-villi associated maternal macrophages (PAMMs) have an unclear role in anti-pathogen defense; however, ex vivo studies suggest that they are microbiocidal, can phagocytose bacteria, and do release pro-inflammatory cytokines following TLR stimulation. Finally, fetal macrophages i.e., Hofbauer cells (HBCs) also have the capacity to secrete pro-inflammatory cytokines following TLR stimulation, can phagocytose pathogens ex vivo and may also use macrophage extracellular nets (METs) to kill bacteria. Whether PAMMs or HBCs employ Fc receptor mediated effector functions has not been explored but represents an intriguing mechanism of anti-pathogen defense given the high concentrations of maternal IgG in the intervillous and intravillious space. Figure was generated using Biorender.