In Tgfb1−/− mice, a murine model of acute Th1-mediated hepatocellular injury, CD11b+Gr1+ cells accumulate in liver in response to the production of IFN-γ from CD4+ T cells. Tgfb1−/− liver CD11b+Gr1+ cells are potent MDSCs in vitro, producing RAD001 solubility dmso NO to inhibit the proliferation of TCR-activated T cells. The production of IFN-γ is important

for the development of the MDSC response at several junctures. First, IFN-γ is required for the accumulation of MDSCs in liver, which does not occur in Ifng−/−Tgfb1−/− mice; second, IFN-γ is required for full MDSC suppressor function, because inclusion of a neutralizing anti–IFN-γ mAb in coculture of MDSCs and T cells partially abrogates suppressor activity. These studies show that IFN-γ is necessary not only for hepatocellular injury but also for the development of the MDSC response. Thus, IFN-γ sits at a critical node of the liver immune response, responsible on one hand for T cell–mediated parenchymal damage and on the other hand for initiating an MDSC-mediated negative feedback pathway that can restrain T cell proliferation. Murine liver schistosomiasis is a classic model of Th2-mediated inflammation, with granulomata forming around Dasatinib solubility dmso parasite eggs deposited in the liver.24, 25 Myeloid cells restrain granulomatous inflammation and fibrosis through activity of arginase,26

which acts by depleting T cells of the essential amino acid L-arginine. By contrast, inflammation and parenchymal damage in Tgfb1−/− mice is a “pure” Th1 phenomenon, dependent on the Th1 cytokine IFN-γ and independent of the Th2 cytokine IL-4.9 Thus, distinct types of inflammation induce distinct subsets of myeloid suppressor cells that act through subset-specific mechanisms. The association of iNOS with myeloid cells in Th1 responses and arginase with myeloid cells in Th2 responses is a recurring theme in inflammation,27 and the dichotomy appears applicable to liver inflammation as well. An important aspect of our

work is the demonstration that Th1 cells themselves are responsible for the accumulation of MDSCs in liver. Although it has been shown that IFN-γ can activate check details MDSCs,28, 29 to our knowledge, this is the first demonstration that IFN-γ from CD4+ T cells can drive MDSC accumulation to a site of inflammation. How might IFN-γ effect MDSC accumulation? Although IFN-γ might act directly, it is more likely that IFN-γ acts indirectly, inducing other cells (e.g. hepatocytes, endothelial cells, Kupffer cells) to secrete chemoattractants that in turn recruit MDSCs. Previous work shows that MDSCs accumulate at sites of inflammation in response to a number of inflammatory molecules. MDSCs isolated from hepatocellular carcinoma tumors in B6 mice express the chemokine (C-C motif) receptor 2 (CCR2) and migrate in vitro in response to the chemokine (C-C motif) ligand 2 (CCL2).