Cationic Amino Acid Transporter-2 Regulates Immunity by Modulating Arginase Activity

Abstract

Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious disease models characterized by the development of polarized Th1 or Th2-type responses. We show that CAT2^−/− mice are significantly more susceptible to the Th1-inducing pathogen Toxoplasma gondii. Although T. gondii infected CAT2^−/− mice developed stronger IFN-γ responses, nitric oxide (NO) production was significantly impaired, which contributed to their enhanced susceptibility. In contrast, CAT2^−/− mice infected with the Th2-inducing pathogen Schistosoma mansoni displayed no change in susceptibility to infection, although they succumbed to schistosomiasis at an accelerated rate. Granuloma formation and fibrosis, pathological features regulated by Th2 cytokines, were also exacerbated even though their Th2 response was reduced. Finally, while IL-13 blockade was highly efficacious in wild-type mice, the development of fibrosis in CAT2^−/− mice was largely IL-13-independent. Instead, the exacerbated pathology was associated with increased arginase activity in fibroblasts and alternatively activated macrophages, both in vitro and in vivo. Thus, by controlling NOS2 and arginase activity, CAT2 functions as a potent regulator of immunity. Recent studies conducted with amino transporter Slc7a2-deficient mice (CAT2) demonstrated that NOS2 activity in macrophages is regulated by CAT2. NOS2, which synthesizes nitric oxide, regulates numerous important activities, including resistance to infectious organisms, tumor development, and autoimmune diseases. It also competes with the enzyme Arginase-1 (Arg1) for the common substrate L-arginine. However, the role CAT2 in the regulation of Arg1 activity has not been previously examined. Therefore, we infected CAT2-deficient mice with the helminth parasite Schistosoma mansoni or with the protozoan pathogen Toxoplasma gondii, two organisms that trigger highly divergent host immune responses. Strikingly, following infection with S. mansoni, CAT2^−/− mice developed parasite egg–induced lesions in the liver that were 3 to 4 times larger than wild type and hepatic fibrosis (a feature of severe schistosomiasis) was exacerbated, indicating a general worsening of disease in the absence of CAT2. The CAT2^−/− mice were also more susceptible to T. gondii infection, demonstrating that CAT2 is critical for the development of protective cell-mediated immunity. Thus, these studies identify CAT2 as a powerful regulator of host immune responses, which may have major implications for a variety of infectious, inflammatory, and autoimmune diseases.