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The outcome of infection with Leishmania major depends in part on the balance between arginase and inducible nitric oxide synthase in macrophages. These enzymes compete for the substrate L-arginine. Leishmania major also encodes an arginase gene but, the role of this parasite-derived enzyme in infection remains unclear. We hypothesize that parasite-derived arginase influences parasite survival and host immune response to L. major. To examine this hypothesis, we employed an arginase deficient null mutant L. major in in vitro and in vivo experiments. Our results show that deficiency of parasite-derived arginase impaired parasite proliferation and disease pathogenesis. Increased arginase activity however neither affected nitric oxide production, nor did it correlate with IL-4 production. Primary infection of normally resistant hosts causes a chronic infection and does not protect them against re-infection. Thus, parasite-derived arginase is of nutritional importance to L. major, but is not a feasible therapeutic drug target.

The outcome of infection with Leishmania major depends in part on the balance between arginase and inducible nitric oxide synthase in macrophages. These enzymes compete for the substrate L-arginine. Leishmania major also encodes an arginase gene but, the role of this parasite-derived enzyme in infection remains unclear. We hypothesize that parasite-derived arginase influences parasite survival and host immune response to L. major. To examine this hypothesis, we employed an arginase deficient null mutant L. major in in vitro and in vivo experiments. Our results show that deficiency of parasite-derived arginase impaired parasite proliferation and disease pathogenesis. Increased arginase activity however neither affected nitric oxide production, nor did it correlate with IL-4 production. Primary infection of normally resistant hosts causes a chronic infection and does not protect them against re-infection. Thus, parasite-derived arginase is of nutritional importance to L. major, but is not a feasible therapeutic drug target.

Células T reguladoras (Treg) são cruciais na tolerância periférica e no controle da inflamação. Nós usamos dois modelos bem estabelecidos de tolerância de mucosas para a asma alérgica e a tolerância inalatória local induzida pela exposição crônica a OVA para estudar o aparecimento e função das Treg. Nós mostramos que a tolerância nasal distinguiu da tolerância oral pela produção sistêmica de IgG1 e desenvolvimento da inflamação alérgica na cavidade peritoneal ou pela indução da inflamação das vias aéreas de camundongos RAG-/- reconstituídos com células T CD4+ após desafios com OVA. Observamos também que Treg Foxp3+ migraram para o pulmão alérgico e expressaram fenótipo de ativação e memória que distinguiu essas células das Treg presentes nos linfonodos drenantes. Células T CD4+CD25+ do pulmão dos animais alérgicos suprimiram a proliferação das células T CD4+CD25-, mas não a produção de citocinas Th2. Finalmente, a exposição crônica a OVA levou ao aumento da apoptose de eosinófilos que infiltraram o pulmão resultando na resolução da inflamação alérgica pulmonar. / Regulatory T cells (Treg) are critical for peripheral tolerance and control of inflammation. We used two well established models of mucosal tolerance to allergic airway disease and the local inhalational tolerance induced by chronic OVA exposure to study the appearance and function of Treg cells. We found that nasal tolerance distinguished from oral tolerance by systemic IgG1 antibody production and development of allergic inflammation in the peritoneal cavity or by induction of airway inflammation in RAG-/- mice reconstituted with CD4+ T cells after OVA challenge. We also found that Foxp3+ T cells migrated to allergic lung and expressed an effector/memory phenotype that distinguished them from Treg cells present in lung draining lymph nodes. Lung infiltrating CD4+CD25+ T cells from allergic mice suppressed CD4+CD25- T cell proliferation but not Th2 cytokines production by these cells. Finally, chronic OVA exposure leaded to increased apoptosis of infiltrating lung eosinophils resulting in the resolution of allergic lung inflammation.

Células T reguladoras (Treg) são cruciais na tolerância periférica e no controle da inflamação. Nós usamos dois modelos bem estabelecidos de tolerância de mucosas para a asma alérgica e a tolerância inalatória local induzida pela exposição crônica a OVA para estudar o aparecimento e função das Treg. Nós mostramos que a tolerância nasal distinguiu da tolerância oral pela produção sistêmica de IgG1 e desenvolvimento da inflamação alérgica na cavidade peritoneal ou pela indução da inflamação das vias aéreas de camundongos RAG-/- reconstituídos com células T CD4+ após desafios com OVA. Observamos também que Treg Foxp3+ migraram para o pulmão alérgico e expressaram fenótipo de ativação e memória que distinguiu essas células das Treg presentes nos linfonodos drenantes. Células T CD4+CD25+ do pulmão dos animais alérgicos suprimiram a proliferação das células T CD4+CD25-, mas não a produção de citocinas Th2. Finalmente, a exposição crônica a OVA levou ao aumento da apoptose de eosinófilos que infiltraram o pulmão resultando na resolução da inflamação alérgica pulmonar. / Regulatory T cells (Treg) are critical for peripheral tolerance and control of inflammation. We used two well established models of mucosal tolerance to allergic airway disease and the local inhalational tolerance induced by chronic OVA exposure to study the appearance and function of Treg cells. We found that nasal tolerance distinguished from oral tolerance by systemic IgG1 antibody production and development of allergic inflammation in the peritoneal cavity or by induction of airway inflammation in RAG-/- mice reconstituted with CD4+ T cells after OVA challenge. We also found that Foxp3+ T cells migrated to allergic lung and expressed an effector/memory phenotype that distinguished them from Treg cells present in lung draining lymph nodes. Lung infiltrating CD4+CD25+ T cells from allergic mice suppressed CD4+CD25- T cell proliferation but not Th2 cytokines production by these cells. Finally, chronic OVA exposure leaded to increased apoptosis of infiltrating lung eosinophils resulting in the resolution of allergic lung inflammation.