Regulation of immune responses by L-arginine metabolism

Abstract

L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate — arginase and nitric-oxide synthase — are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.

Key Points

  • An impaired balance between immature and mature myeloid cells is one of the hallmarks of seemingly unrelated pathological conditions that are associated with T-cell dysfunction.

  • In mice, co-expression of CD11b and GR1 is associated with myeloid cells at various stages of differentiation that can inhibit T-cell activation induced by either antigen or a polyclonal stimulus. This inhibition occurs through an MHC-independent mechanism that requires cell–cell contact.

  • These myeloid cells are known as myeloid suppressor cells (MSCs), and they partially overlap with the previously described natural suppressor cells. MSCs arise from bone marrow and other haematopoietic organs that are exposed to systemically released factors that act on myelomonocytic precursors.

  • MSCs inhibit antigen-activated T cells by a mechanism that requires important enzymes of L-arginine metabolism, the inducible forms of nitric-oxide synthase (NOS) and arginase (ARG), NOS2 and ARG1. In mouse myeloid cells, NOS2 and ARG1are competitively regulated by T helper 1 (TH1) and TH2 cytokines, respectively.

  • MSCs can use ARG1 and NOS2, either separately or in combination, to restrain T-cell functions. The choice is regulated by a network of signals, cytokines and receptor–ligand interactions that underlie the crosstalk between MSCs and activated T cells.

  • NOS2 generates nitric oxide (NO), which blocks signalling from the interleukin-2 receptor. By contrast, L-arginine depletion induced by the activity of ARG1 causes downregulation of expression of the ζ-chain of CD3 and, consequently, impairment of its signalling properties.

  • Moreover, NO and superoxide (O2) production in MSCs generates several highly oxidizing molecules known as reactive nitrogen and oxygen species. Generation of reactive nitrogen and oxygen species regulates the contraction phase of CD8+ T cells following antigenic stimulation.

  • The activity of ARG1 and NOS2 working in combination was recently described for CD11b+GR1+ cells from tumour-bearing mice and chronically infected mice, thereby indicating that co-expression of both enzymes could be unique to MSCs.

  • Evidence from animal and human models indicates that the immunomodulatory role of L-arginine metabolism is important in physiological, as well as pathological, conditions, which provides the rationale for development of therapeutic compounds that control the ARG and NOS enzymatic pathways.

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Figure 1: Schematic representation of arginase-1- and nitric-oxide-synthase-2-dependent metabolic pathways.
Figure 2: Cytokine-dependent and metabolic regulatory circuits that affect the inducible enzymes arginase 1 and nitric-oxide synthase 2.
Figure 3: Potential pathways controlling the T-cell response to L-arginine metabolism.
Figure 4: A model for the immunopathological consequences of myeloid-suppressor-cell activity.

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Acknowledgements

This work was supported by grants for Finalized Research from the Italian Ministry of Health, and from the Oncology Strategic Project of the Ministry of Education, University and Research National Research Council (MIUR-CNR), the Basic Research Fund of the Ministry of Education, University and Research (FIRB-MIUR) and the Italian Association for Cancer Research (AIRC). We thank A. Azzalini for assistance with graphic preparation, and we apologize to authors whose work was not cited as a consequence of space restrictions.

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Correspondence to Vincenzo Bronte.

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DATABASES

Entrez Gene

ARG1

ARG2

CD11b

CD31

GR1

NOS1

NOS2

ODC

FURTHER INFORMATION

Department of Oncological and Surgical Sciences

Glossary

ACCESSORY CELL

A cell that is required for, but does not itself mediate, a specific immune response. These cells intervene in different phases of an immune response, from priming to generating immunological memory. The term is often used to describe antigen-presenting cells, which are specialized cells that are involved in processing and presentation of antigen to lymphocytes.

REACTIVE OXYGEN SPECIES (ROS).

Aerobic organisms derive their energy from the reduction of oxygen (O2). The metabolism of O2, and in particular its reduction through the mitochondrial electron-transfer chain, generates byproducts such as superoxide (O2), hydrogen peroxide (H2O2) and hydroxyl radicals (OH). These three species and the unstable intermediates that are formed by lipid peroxidation are referred to as ROS. ROS can damage important intracellular targets, such as DNA, carbohydrates or proteins.

tRNA

A small RNA molecule that carries specific amino acids to the ribosome for polymerization into a polypeptide chain. During translation, an amino acid is inserted into the growing polypeptide chain when the anticodon of a tRNA pairs with a codon on the mRNA being translated.

REACTIVE NITROGEN-OXIDE SPECIES (RNOS).

Nitric oxide (NO) chemistry is complex because of the extreme reactivity of NO, which can result in the formation of different reactive nitrogen intermediates (RNI) depending on the amount of NO that is produced by cells. At low concentrations, NO reacts directly with metals and radicals. At higher concentrations, indirect effects prevail, and these include several oxidation or nitrosylation reactions with oxygen (O2) that result in the production of various moieties. NO and related RNI are effective antimicrobial agents and signal-transducing molecules. The term RNOS, although less frequently used, more specifically indicates this family of molecules than does the term RNI.

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