Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy.
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.
Kropf
Pascale
P
Department of Immunology, Faculty of Medicine, Imperial College London, London, UK.
Baud
David
D
Marshall
Sara E
SE
Munder
Markus
M
Mosley
Angelina
A
Fuentes
José M
JM
Bangham
Charles R M
CR
Taylor
Graham P
GP
Herath
Shanti
S
Choi
Beak-San
BS
Soler
Germán
G
Teoh
Tg
T
Modolell
Manuel
M
Müller
Ingrid
I
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
D011257:Pregnancy Proteins; D001120:Arginine; D001119:Arginase