In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseases. Our work is focused on elucidating the mechanisms of granulomatous inflammation, fibrosis, portal hypertension, and death following infection with S. mansoni and to devise novel strategies to slow or reverse the progression of liver fibrosis. Progress was made in the following area: Modulation of T cell responses in both normal and inflamed tissue prevents immunopathology and horror autotoxicus self-reactivity. Among the many interlocking pathways that can suppress T cell proliferation and activity, myeloid cell-mediated amino acid deprivation is a key checkpoint in preventing immunopathology. For example, both tryptophan and arginine are essential for T cell growth and function, and their local degradation by indoleamine oxidases (IDO1 and IDO2) or arginase 1 (Arg1) and possibly arginase 2 (Arg2) expressed in myeloid cells restrains T cell proliferation, limits tissue damage, and contributes to immunologic tolerance. Amino acid starvation is also a medically important strategy to target cells auxotrophic for specific amino acids. For example, asparaginase deprives leukemic cells of their exogenous supply of asparagine, and the fungal metabolite halofuginone blocks pathogenic TH17 responses by interfering with the glutamyl-prolyl tRNA synthase causing an amino acid stress response. Arginine and tryptophan degradation pathways are linked to malignancy and chronic infections, where tumors and pathogens subvert the host's T cell control pathways to suppress productive immune responses. Amino acid metabolism is also linked to Treg development and stability at sites of infection via a process termed infectious tolerance, which is a self-reinforcing pathway aiding in tissue resolution and repair following inflammation. The liver immune response to Schistosoma mansoni eggs is an example of how myeloid cells exert control over T cells through amino acid metabolism. In murine and human schistosomiasis, worm eggs lodged in the liver drive a TH2-mediated asynchronous granulomatous response characterized by collagen deposition and fibrosis, all of which are required to wall off the eggs, which are highly toxic. The fibrotic granulomas protect the surrounding tissues from damage caused by the toxic eggs until they can be degraded. The TH2 response recruits inflammatory Ly6C+ monocytes from the blood to granulomas; there they differentiate into macrophages and become activated by IL-4 and IL-13 to the alternatively activated or M2 pathway. In this context, M2 macrophages express high amounts of the arginine hydrolase Arg1 regulated via the IL-4- and IL-13-induced STAT6 pathway. When mice lacking Arg1 specifically in macrophages were infected with schistosomes, an unregulated TH2 response occurred leading to a failure to down-regulate the pro-fibrotic response, excessive production of IL-4 and IL-13, hepatomegaly, and early lethality. However, when eggs are artificially introduced into the lung via intravenous administration, a TH2 pro-fibrotic response occurs independent of macrophage Arg1. Lung tissue contains little arginase activity, whereas liver hepatocytes express high and constitutive Arg1 as part of the urea cycle, which eliminates excess nitrogen via urea. Because Arg1 catalyzes the same biochemical degradation of arginine in hepatocytes and macrophages, and because granulomas are embedded in the Arg1-rich hepatocyte parenchyma, we hypothesized that microenvironmental arginine depletion by macrophage Arg1 close to the granuloma nucleus is the key step in restricting T cell activity, thus blocking excessive immune responses. In this study we developed an in vitro cellular biochemistry system to explore the mechanistic basis of microenvironmental arginine depletion sensing by T cells. We showed that the nutrient recognition pathway Rictor/mTORC2 is the central mechanisms by which T cells measure environmental arginine.
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