Regulation of immune responses by L-arginine metabolism

Abstract

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 (T_H1) and T_H2 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.