Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1.
Highlights
Immune reactions are a fine balance between activation and suppression
We confirmed Tdo2 expression in the early phases of gestation [15, 31], starting around day E3.5, peaking at day E6.5 and contracting progressively until day E12.5, when it reached a basal level that remained stable until the gestation end (Figure 1A). This Tdo2 expression was absent in placenta from TDO-KO females, indicating that it was mostly contributed by maternal tissues
IHC stainings of TDO with our chimeric rabbit antibody on the same samples confirmed the RT-qPCR results, with a massive TDO expression observed around days E5.5 and E7.5 and localized in the decidualized endometrium, which is the maternal part of the placenta (Figure 1B)
Summary
Immune reactions are a fine balance between activation and suppression. essential for the elimination of pathogens, they can be destructive, e.g., by targeting paternal antigens in embryos. The placenta sets up several defense mechanisms to prevent recognition of paternal antigens and immune-mediated embryo rejection [1, 2]. The placenta induces the expression of enzymes that inhibit lymphocyte activity and proliferation by degrading the essential amino acid tryptophan [2]. Under non-inflammatory conditions, IDO1 is expressed in scattered cells in the lung, female genital tract and secondary lymphoid organs [6]. It is highly expressed in placenta and tumors [6], which were shown to benefit from its immunosuppressive function [10, 11]. These results led to the development of IDO1 inhibitors that are currently in clinical development [22]
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