L-arginine metabolism in myeloid cells controls T-lymphocyte functions

doi:10.1016/S1471-4906(03)00132-7

Trends in Immunology

Volume 24, Issue 6, June 2003, Pages 301-305

https://doi.org/10.1016/S1471-4906(03)00132-7 Get rights and content

Abstract

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.

Section snippets

L-arginine metabolism in MSCs: arginase and nitric oxide synthase

Recent studies of the inhibitory pathways involved in MSC-mediated immune suppression have shown that MSCs exploit the metabolism of L-arginine (L-Arg) to render lymphocytes unresponsive to antigen stimulation. L-Arg is metabolized by myeloid cells (macrophages, granulocytes and DCs) by two enzymes: (1) nitric oxide synthase (NOS), which oxidizes L-Arg in two steps that generate NO and citrulline; and (2) arginase, which converts L-Arg into urea and L-ornithine 8, 9 (Fig. 1). Separate genes

NOS2 blocks T-cell function by interfering with the IL-2 pathway

Induction of NOS2 alone in MSCs, with subsequent release of NO, is responsible for inhibition of T-cell responses in some experimental settings, demonstrated by complete reversal of immunosuppression with specific NOS2 inhibitors 13, 14, 15, 16. Moreover, NO, when added directly to cultures, is an extremely potent inhibitor of T-cell proliferation. IFN-γ released by activated T lymphocytes and a yet to be identified contact between T lymphocytes and MSCs is necessary for NO production and

Arg1 depletes L-Arg from the local environment

Depletion of nutrients, such as L-Arg, is a strategy used throughout nature to control growth of organisms competing for the same biological niche. Lower organisms exploit L-Arg starvation as a strategy for survival, by using their own arginase or taking advantage of the derived enzyme of the host (reviewed in Ref. [22]). Higher organisms have evolved to use localized L-Arg starvation to control the growth of particular cell types, for example, T lymphocytes in higher vertebrates. L-Arg

Arg1 and NOS2 synergism in MSC-dependent suppression

In macrophages, Thl cytokines induce NOS2 but inhibit Arg1, whereas the reverse is true for Th2 cytokines 34, 35. This reciprocal regulation is also promoted by biochemical feedback mechanisms: NOHA, a byproduct of the conversion of L-Arg to NO by NOS2, inhibits arginase [36], whereas L-Arg depletion by Arg1 can limit NOS2-dependent synthesis of NO. Also, polyamines, final products of the Arg1–ornithine decarboxylase (ODC) pathway, downregulate NOS2 expression 12, 37 (Fig. 1). Because Th1

Conclusion and therapeutic perspectives

It is probable that the main function of MSCs in vivo is in the restraint of runaway immune responses, however, in some cases, MSC might favour disease progression, for example, MSCs frequently hinder anti-tumor T-cell responses. Drugs controlling Arg1 and NOS2, the enzymes mediating suppression in MSCs, might, therefore, represent a novel class of immune modulators that would act by limiting the effects of MSC activity in vivo. Such drugs could be used in combination with cancer vaccines for

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Trends in Immunology

L-arginine metabolism in myeloid cells controls T-lymphocyte functions

Abstract

Section snippets

L-arginine metabolism in MSCs: arginase and nitric oxide synthase

NOS2 blocks T-cell function by interfering with the IL-2 pathway

Arg1 depletes L-Arg from the local environment

Arg1 and NOS2 synergism in MSC-dependent suppression

Conclusion and therapeutic perspectives

Blood

J. Biol. Chem.

Trends Parasitol.

Immunol. Today

J. Biol. Chem.

Pulm. Pharmacol. Ther.

Trends Immunol.

J. Biol. Chem.

Tumor-induced immune dysfunctions caused by myeloid suppressor cells

J. Immunother.

Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells

J. Immunol.

Unopposed production of granulocyte–macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation

J. Immunol.

Immature myeloid cells and cancer-associated immune suppression

Cancer Immunol. Immunother.

Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance

Proc. Natl. Acad. Sci. U. S. A.

CD8(+) tumor-infiltrating T cells are deficient in perforin-mediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis

J. Immunol.

Arginine metabolism: nitric oxide and beyond

Biochem. J.

Nitric oxide and the immune response

Nat. Immunol.

Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells

Am. J. Physiol.

Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide

Am. J. Physiol.

Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway

J. Immunol.

Immune suppression by recombinant interleukin (rIL)-12 involves interferon γ induction of nitric oxide synthase 2 (iNOS) activity: inhibitors of NO generation reveal the extent of rIL-12 vaccine adjuvant effect

J. Exp. Med.

Early myeloid cells are high producers of nitric oxide upon CD40 plus IFN-γ stimulation through a mechanism dependent on endogenous TNF-α and IL-1α

Eur. J. Immunol.

Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism

J. Immunol.

Apoptotic death of CD8⁺ T lymphocytes after immunization: induction of a suppressive population of Mac-1⁺/Gr-1⁺ cells

Unopposed production of granulocyte–macrophage colony-stimulating factor by tumors inhibits CD8⁺ T cell responses by dysregulating antigen-presenting cell maturation