Arginase-2 dampens fetal immunity: Fetal dendritic cells give mum a break

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Gestation is an extraordinary exercise in mutual tolerance. Mother and fetus expressing different histocompatibility molecules coexist for months in intimate tissue contact without mutual rejection. A recent paper by McGovern et al.1 provides new clues on the mechanisms that make this coexistence possible. They report that human fetal dendritic cells (DC) express high levels of the enzyme Arginase-2 and inhibit tumor necrosis factor α (TNFα) production by allogeneic T cells in vitro (Figure 1). Thus, Arginase-2 may represent a new component in the regulation of maternal-fetal immune equilibrium and fetal immune responses overall.
The question of fetal and neonatal immune reactivity has puzzled immunologists for a long time. Initial experiments suggested that their immature immune systems are especially predisposed to tolerance. These were followed by more quantitative studies showing that if the dose of immunogen was appropriately adjusted to the smaller size of the recipient, neonatal immune responses could be observed. There were, however, frequent exceptions. Moreover, neonatal immune responses were different from adult ones, with a ‘Th2 bias' often being apparent.2
The new paper by McGovern et al. uses advanced flow cytometry, transcriptomics and cell culture to carry out an in-depth analysis of fetal DC populations at different times of gestational development. The authors report that, from about week 18 of gestation, human fetal DC were normally distributed in lymphoid tissues, able to migrate to lymph nodes and comprised subsets that closely reflected the adult ones. Fetal DC also appeared functionally similar to adult DC as they were similarly able to respond to toll-like receptor (TLR) ligands and induce the proliferation of adult T cells in vitro. However, consistent with previous reports, fetal DC were less efficient than adult DC at eliciting the production of several pro-inflammatory cytokines by co-cultured T cells, inducing more IL4 and more regulatory T cells (Tregs) instead. As might be expected given these findings, a comparison of the transcriptional profile of fetal and adult DC revealed a large number of differentially expressed genes, and pathway analysis finally lead the authors to the enzyme Arginase-2.
Arginases are immunoregulatory enzymes that can act in a cell-autonomous or bystander fashion, catabolizing the amino acid l-arginine and reducing its availability in the local environment.3 L-arginine is important for a number of cell functions: as a building block for protein synthesis, and especially as an intermediate in the production of many metabolites, including the antibacterial molecule nitric oxide in activated macrophages. l-arginine also has broad effects on T cells, supporting oxidative phosphorylation during naïve T-cell activation and promoting the development of memory T cells and antitumor effector function.4 The function of arginases in DC has not been explored in detail, but we know that enforced expression of Arginase-2 in monocyte-derived DC can decrease antigen-specific T-cell proliferation in vitro and in vivo.5 McGovern et al. show that neutralizing arginase activity in fetal DC cultures (by adding excess l-arginine or arginase inhibitors) can rescue production of the pro-inflammatory cytokine TNFα in adult and fetal T cells. Remarkably, the effects of arginases are restricted to TNFα; altered T-cell production of other cytokines is not rescued by arginase neutralization. These results strongly support a functional role of Arginase-2 in fetal DC. How Arginase-2 is differentially regulated in fetal vs adult DC, and the precise mechanism by which this specifically affects TNFα production by T cells remains to be defined. Similarly, whether it influences DC, Tregs or other cells is still unclear. Importantly, the potential impact of TNFα-producing T cells, if activated, on fetal health also remains to be established. Experiments with mice will probably be necessary to answer some of these questions.
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