IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice.
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.
Bronte
Vincenzo
V
Department of Oncology and Surgical Sciences, University of Padua, Padua, Italy. enzo.bronte@unipd.it
Serafini
Paolo
P
De Santo
Carmela
C
Marigo
Ilaria
I
Tosello
Valeria
V
Mazzoni
Alessandra
A
Segal
David M
DM
Staib
Caroline
C
Lowel
Marianne
M
Sutter
Gerd
G
Colombo
Mario P
MP
Zanovello
Paola
P
D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D004790:Enzyme Induction / Q000276:immunology; D005260:Female; D006131:Growth Inhibitors / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010088:Oxidoreductases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013481:Superoxides / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D013481:Superoxides; D015847:Interleukin-4; D010088:Oxidoreductases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase