L-arginine metabolism in myeloid cells controls T-lymphocyte functions.
Although current attention has focused on regulatory T lymphocytes as suppressors of autoimmune responses, powerful immunosuppression is also mediated by a subset of myeloid cells that enter the lymphoid organs and peripheral tissues during times of immune stress. If these myeloid suppressor cells (MSCs) receive signals from activated T lymphocytes in the lymphoid organs, they block T-cell proliferation. MSCs use two enzymes involved in arginine metabolism to control T-cell responses: inducible nitric oxide synthase (NOS2), which generates nitric oxide (NO) and arginase 1 (Arg1), which depletes the milieu of arginine. Th1 cytokines induce NOS2, whereas Th2 cytokines upregulate Arg1. Induction of either enzyme alone results in a reversible block in T-cell proliferation. When both enzymes are induced together, peroxynitrites, generated by NOS2 under conditions of limiting arginine, cause activated T lymphocytes to undergo apoptosis. Thus, NOS2 and Arg1 might act separately or synergistically in vivo to control specific types of T-cell responses, and selective antagonists of these enzymes might prove beneficial in fighting diseases in which T-cell responses are inappropriately suppressed. This Opinion is the second in a series on the regulation of the immune system by metabolic pathways.
Bronte
Vincenzo
V
Department of Oncology and Surgical Sciences, Via Gattamelata 64, 35128, Padua, Italy. enzo.bronte@unipd.it
Serafini
Paolo
P
Mazzoni
Alessandra
A
Segal
David M
DM
Zanovello
Paola
P
D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D013491:Suppressor Factors, Immunologic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D007376:Interleukin-2; D013491:Suppressor Factors, Immunologic; D001120:Arginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D001119:Arginase