title: 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 CD3 zeta, 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 CD3 zeta 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.
authors.affiliation: Department of Immunology, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Pascale
authors.initials: P
authors.lastname: Kropf
authors.forename: David
authors.initials: D
authors.lastname: Baud
authors.forename: Sara E
authors.initials: SE
authors.lastname: Marshall
authors.forename: Markus
authors.initials: M
authors.lastname: Munder
authors.forename: Angelina
authors.initials: A
authors.lastname: Mosley
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.forename: Shanti
authors.initials: S
authors.lastname: Herath
authors.forename: Beak-San
authors.initials: BS
authors.lastname: Choi
authors.forename: Germán
authors.initials: G
authors.lastname: Soler
authors.forename: Tg
authors.initials: T
authors.lastname: Teoh
authors.forename: Manuel
authors.initials: M
authors.lastname: Modolell
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
mesh_terms: D000328:Adult; D001119:Arginase / Q000096:biosynthesis / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D011257:Pregnancy Proteins; D001120:Arginine; D001119:Arginase