IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice

Vincenzo Bronte, Paolo Serafini, Carmela De Santo, Ilaria Marigo, Valeria Tosello, Alessandra Mazzoni, David M. Segal, Caroline Staib, Marianne Lowel, Gerd Sutter, Mario P. Colombo, Paola Zanovello

Research output: Contribution to journalArticle

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-γ 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.

Original languageEnglish
Pages (from-to)270-278
Number of pages9
JournalJournal of Immunology
Volume170
Issue number1
Publication statusPublished - Jan 1 2003

ASJC Scopus subject areas

  • Immunology

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    Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., Mazzoni, A., Segal, D. M., Staib, C., Lowel, M., Sutter, G., Colombo, M. P., & Zanovello, P. (2003). IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. Journal of Immunology, 170(1), 270-278.