CTLA-4 blockage increases resistance to infection with the intracellular protozoan Trypanosoma cruzi.
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.
Martins
Gislâine Aparecida
GA
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Tadokoro
Carlos Eduardo
CE
Silva
Roberta Borges
RB
Silva
João Santana
JS
Rizzo
Luiz Vicente
LV
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
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