title: CTLA-4 blockage increases resistance to infection with the intracellular protozoan Trypanosoma cruzi.
abstract: Recent studies have revealed an important role for CTLA-4 as a negative regulator of T cell activation. In the present study, we evaluated the importance of CTLA-4 to the immune response against the intracellular protozoan, Trypanosoma cruzi, the causative agent of Chagas' disease. We observed that the expression of CTLA-4 in spleen cells from naive mice cultured in the presence of live trypomastigote forms of T. cruzi increases over time of exposure. Furthermore, spleen cells harvested from recently infected mice showed a significant increase in the expression of CTLA-4 when compared with spleen cells from noninfected mice. Blockage of CTLA-4 in vitro and/or in vivo did not restore the lymphoproliferative response decreased during the acute phase of infection, but it resulted in a significant increase of NO production in vivo and in vitro. Moreover, the production of IFN-gamma in response to parasite Ags was significantly increased in spleen cells from anti-CTLA-4-treated infected mice when compared with the production found in cells from IgG-treated infected mice. CTLA-4 blockade in vivo also resulted in increased resistance to infection with the Y and Colombian strains of T. cruzi. Taken together these results indicate that CTLA-4 engagement is implicated in the modulation of the immune response against T. cruzi by acting in the mechanisms that control IFN-gamma and NO production during the acute phase of the infection.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Gislâine Aparecida
authors.initials: GA
authors.lastname: Martins
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Tadokoro
authors.forename: Roberta Borges
authors.initials: RB
authors.lastname: Silva
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
authors.forename: Luiz Vicente
authors.initials: LV
authors.lastname: Rizzo
mesh_terms: D000208:Acute Disease; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma