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.     

Induced arginine transport via cationic amino acid transporter‐1 is necessary for human T‐cell proliferation

Availability of the semiessential amino acid arginine is fundamental for the efficient function of human T lymphocytes. Tumor‐associated arginine deprivation, mainly induced by myeloid‐derived suppressor cells, is a central mechanism of tumor immune escape from T‐cell‐mediated antitumor immune responses. We thus assumed that transmembranous transport of arginine must be crucial for T‐cell function and studied which transporters are responsible for arginine influx into primary human T lymphocytes. Here, we show that activation via CD3 and CD28 induces arginine transport into primary human T cells. Both naïve and memory CD4⁺ T cells as well as CD8⁺ T cells specifically upregulated the human cationic amino acid transporter‐1 (hCAT‐1), with an enhanced and persistent expression under arginine starvation. When hCAT‐1 induction was suppressed via siRNA transfection, arginine uptake, and cellular proliferation were impaired. In summary, our results demonstrate that hCAT‐1 is a key component of efficient T‐cell activation and a novel potential target structure to modulate adaptive immune responses in tumor immunity or inflammation.     

L‐Arginine deprivation impairs Leishmania major‐specific T‐cell responses

The amino acid L ‐arginine plays a crucial role in the regulation of immune responses. We have recently shown that uncontrolled replication of Leishmania parasites at the site of pathology correlates with high levels of arginase activity in nonhealing leishmaniasis and that this elevated arginase activity causes local depletion of L ‐arginine. To further our understanding of the impact of L ‐arginine deprivation in experimental leishmaniasis, here we characterize in detail the effects of L ‐arginine deprivation on antigen‐specific T cells and MΦ. The results of our study show that decrease of L ‐arginine levels in the extracellular milieu affects the biological activities of Leishmania major‐specific T cells, both at the level of the magnitude and the quality of their responses. L. major‐specific CD4⁺ T cells rendered hyporesponsive by L ‐arginine deprivation can be partially rescued by addition of exogenous L ‐arginine to produce IL‐4 and IL‐10, but not to produce IFN‐γ. Furthermore, our results show that L ‐arginine deprivation also greatly impacts parasite growth in activated macrophages. In summary, our results suggest that L ‐arginine levels affect both Th cell responses and parasite replication.     

Arginase: an emerging key player in the mammalian immune system

The enzyme arginase metabolizes L-arginine to L-ornithine and urea. Besides its fundamental role in the hepatic urea cycle, arginase is also expressed the immune system of mice and man. While significant interspecies differences exist regarding expression, subcellular localization and regulation of immune cell arginase, associated pathways of immunopathology are comparable between species. Arginase is induced in murine myeloid cells mainly by Th2 cytokines and inflammatory agents and participates in a variety of inflammatory diseases by down-regulation of nitric oxide synthesis, induction of fibrosis and tissue regeneration. In humans, arginase I is constitutively expressed in polymorphonuclear neutrophils and is liberated during inflammation. Myeloid cell arginase-mediated L-arginine depletion profoundly suppresses T cell immune responses and this has emerged as a fundamental mechanism of inflammation-associated immunosuppression. Pharmacological interference with L-arginine metabolism is a novel promising strategy in the treatment of cancer, autoimmunity or unwanted immune deviation.     

Tissue engineering of bone

Despite well-established bone-grafting techniques, large bone defects still represent a challenge for orthopaedic and reconstructive surgeons. Efforts have therefore been made to develop osteoconductive, osteoinductive and osteogenic bone-replacement systems. According to its original definition, tissue engineering is an 'interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function'. It is based on the understanding of tissue formation and regeneration, and aims to grow new functional tissues rather than to build new spare parts. This review focuses on the principles of tissue engineering applied to the creation of bioartificial bone tissue. Important aspects, such as osteogenic cells, matrix materials, inter- and intra-cellular communication, growth factors, gene therapy and current concepts of bone tissue engineering are reviewed. First clinical applications are discussed. An outlook provides insight into the possible future perspectives of bone tissue engineering.