IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice - PubMed (original) (raw)

. 2003 Jan 1;170(1):270-8.

doi: 10.4049/jimmunol.170.1.270.

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

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

Vincenzo Bronte et al. J Immunol. 2003.

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.

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