Abstract
Complex regulation of T cell functions during pregnancy is required to ensure materno-fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate l-arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase-mediated l-arginine depletion induces down-regulation of CD3ζ, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase-mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous l-arginine restored CD3ζ chain expression and T cell proliferation. Thus, l-arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy.
Highlights
The success of pregnancies poses an unresolved immunological challenge: the survival of the semi-immaturity of the fetus, and suppression or modification of the maternal immune system during pregnancy
We show that high arginase activity is present in cells isolated from placenta, and that the source of arginase is mainly neutrophils and a population of alternatively activated macrophages
This is supported by down-regulation of CD3f chain expression in TCR+ PlaC, a finding consistently associated with L-arginine depletion [20, 21, 29]
Summary
The success of pregnancies poses an unresolved immunological challenge: the survival of the semi-immaturity of the fetus, and suppression or modification of the maternal immune system during pregnancy. The placenta uniquely expresses allogeneic antigens and there is evidence that control or tolerization of anti-fetal T cells is critical [3]. Transient suppression of the maternal immune response is necessary for fetal survival, and it is likely that several interconnected mechanisms have evolved to prevent rejection of the fetus. The inhibitory T cell costimulatory molecule programmed cell death ligand 1 has been shown to play a critical role in preventing maternal immune responses against the fetus and increasing apoptosis of T cells was considered as a potential mechanism [5]. Indoleamine 2,3 dioxgenase (IDO), a tryptophan-catabolizing enzyme expressed in macrophages, dendritic cells and extravillous trophoblasts has been identified as one of the mechanisms that plays a role in induction of tolerance and maintenance of allogeneic pregnancies [12,13,14]. In the work we present here we have identified a novel pathway for the temporary suppression of immune responses in normal pregnancies
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