Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy

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.

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

“…Similar to observations resulting from Trp metabolism, Arg catabolism was proposed as a mechanism involved in fetal tolerance, after ARG1 activity was shown to be increased in normal term pregnancy (29). Increased Arg catabolism induced T cell hyporesponsiveness through a mechanism involving reduced half-life of mRNA encoding the TCR CD3j chain (30).…”

Depletion ofL-arginine induces autophagy as a cytoprotective response to endoplasmic reticulum stress in human T lymphocytes

“…Arginase level has been reported to be significantly increased in the peripheral blood of pregnant women and placenta, leading to the temporary suppression of the maternal immune response during human pregnancy. 8 High levels of arginase activity have been suggested to contribute to T cell dysfunction in human immunodeficiency virus-seropositive patients. 9 High arginase activity, a hallmark of nonhealing leishmaniasis, is primarily expressed locally at the site of pathology and causes local depletion of L-Arg, resulting in impaired T cell responses.…”

Estrogen Receptors in Leukocytes - Possible Impact on Inflammatory Processes in the Female Reproductive System

“…The symbiosis between mother and fetus during pregnancy is not due to immunological ignorance, but a complex transient modulation of the maternal immune response where the adaptive immunity is down-modulated and the innate immune response is enhanced (Muller et al, 2009). It has been reported that there is a temporary suppression of maternal T cell responses by arginase secreted by polymorphonuclear leukocytes in normal pregnancies (Kropf et al, 2007). Thus, there is interplay between the different types of leukocytes to protect the fetus from the maternal immune system.…”