Abstract
Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect fetal antigens from maternal effector cells. Their effect is associated with the up-regulation of tolerance-associated molecules at the fetal-maternal interface. Among these, Heme Oxygenase-1 (HO-1, coded by Hmox1) is of special importance as its blockage correlates with increased abortion rates and its up-regulation positively affects pregnancy outcome. Here, we aimed to investigate whether the protective effect of Treg is mediated by HO-1 in a mouse model. HO-1 blockage by Zinc Protoporhyrin (ZnPPIX) abrogated the protective effect of Treg transfer. We found that HO-1 is important in maintaining maternal dendritic cells (DCs) in an immature state, which contributes to the expansion of the peripheral Treg population. This brings to light one essential pathway through which Treg mediates the semi-allogeneic fetus tolerance.
Highlights
The survival of a developing fetus is a complex process whose success is achieved with stringent tolerance of maternal immune system towards the allogeneic paternal antigens expressed by fetal structures such as the placenta [1]
We confirmed that low Heme oxygenase-1 (HO-1) protein levels, as it occurs naturally in AP mice, correlate inversely with abortion rates (r2 = 0.3134, p = 0.0155), while high HO-1 levels in normal pregnancies (NP) mice are associated with low abortion rates (Fig. 1B)
The difference in HO-1 expression in placental tissue between NP and AP mice seems to be dictated by the paternal component, which is the only genetic difference between both F1 tissues as DBA/2J males present significantly lower Hmox1 mRNA levels in several tissues when compared to BALB/c males
Summary
The survival of a developing fetus is a complex process whose success is achieved with stringent tolerance of maternal immune system towards the allogeneic paternal antigens expressed by fetal structures such as the placenta [1]. Some of current theories as to how the maternal immune system actively tolerates the fetus include fetal tissue depletion of tryptophan, an essential amino acid necessary for rapidly dividing cells thereby hindering T cell proliferation [4], expression of human leukocyte antigen G (HLA-G) which blocks the activation of natural killer cells [5], a shift to a Th2 cytokine profile [6] and apoptosis of maternal activated lymphocytes due to the trophoblastic expression of Fas ligand [7] None of these alone can explain fetal survival as IDO [8], FAS [9] and IL-10/IL-4 [10] as well as IL-4/IL-5/IL-9/IL-13 combined [11] knockout mice have normal pregnancy outcome. A special subset of T cells, regulatory T cells (Treg) [12] has been revelead as important for the survival, acceptance and immune tolerance of developing fetuses [13,14,15,16]
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