Abstract
We previously demonstrated that a specialized subset of immature myeloid cells migrate to lymphoid organs as a result of tumor growth or immune stress, where they suppress B and T cell responses to Ags. Although NO was required for suppression of mitogen activation of T cells by myeloid suppressor cells (MSC), it was not required for suppression of allogenic responses. In this study, we describe a novel mechanism used by MSC to block T cell proliferation and CTL generation in response to alloantigen, which is mediated by the enzyme arginase 1 (Arg1). We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4 in freshly isolated MSC or cloned MSC lines, and is therefore up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is induced by IFN-gamma and Th1 cells. Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arginase / biosynthesis*
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Arginase / metabolism
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Arginase / physiology*
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Cell Division / immunology
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Clone Cells
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Cytotoxicity, Immunologic*
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Down-Regulation / immunology*
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Enzyme Induction / immunology
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Female
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Growth Inhibitors / physiology
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Immunosuppressive Agents / pharmacology*
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Interleukin-4 / deficiency
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Interleukin-4 / genetics
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Interleukin-4 / pharmacology
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Interleukin-4 / physiology*
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Knockout
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Myeloid Cells / enzymology
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Myeloid Cells / immunology
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Oxidoreductases / metabolism
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Protein Structure, Tertiary
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Spleen / cytology
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Spleen / immunology
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Superoxides / metabolism
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Cytotoxic / enzymology
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T-Lymphocytes, Cytotoxic / immunology
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Th2 Cells / immunology
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Tumor Cells, Cultured
Substances
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Growth Inhibitors
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Immunosuppressive Agents
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Superoxides
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Interleukin-4
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Oxidoreductases
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Arginase