title: Impaired innate immunity in Tlr4(-/-) mice but preserved CD8+ T cell responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice.
abstract: The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-gamma secreting CD8+ T cells specific for H-2K(b)-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2(-/-), Tlr4(-/-), Tlr9(-/) (-) or Myd88(-/-) mice generated both specific cytotoxic responses and IFN-gamma secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-gamma+CD4+ cells was diminished in infected Myd88(-/-) mice. We also analyzed the efficiency of TLR4-driven immune responses against T. cruzi using TLR4-deficient mice on the C57BL genetic background (B6 and B10). Our studies demonstrated that TLR4 signaling is required for optimal production of IFN-gamma, TNF-alpha and nitric oxide (NO) in the spleen of infected animals and, as a consequence, Tlr4(-/-) mice display higher parasitemia levels. Collectively, our results indicate that TLR4, as well as previously shown for TLR2, TLR9 and MyD88, contributes to the innate immune response and, consequently, resistance in the acute phase of infection, although each of these pathways is not individually essential for the generation of class I-restricted responses against T. cruzi.
authors.affiliation: Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ana-Carolina
authors.initials: AC
authors.lastname: Oliveira
authors.forename: Bruna C
authors.initials: BC
authors.lastname: de Alencar
authors.forename: Fanny
authors.initials: F
authors.lastname: Tzelepis
authors.forename: Weberton
authors.initials: W
authors.lastname: Klezewsky
authors.forename: Raquel N
authors.initials: RN
authors.lastname: da Silva
authors.forename: Fabieni S
authors.initials: FS
authors.lastname: Neves
authors.forename: Gisele S
authors.initials: GS
authors.lastname: Cavalcanti
authors.forename: Silvia
authors.initials: S
authors.lastname: Boscardin
authors.forename: Marise P
authors.initials: MP
authors.lastname: Nunes
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Santiago
authors.forename: Alberto
authors.initials: A
authors.lastname: Nóbrega
authors.forename: Maurício M
authors.initials: MM
authors.lastname: Rodrigues
authors.forename: Maria
authors.initials: M
authors.lastname: Bellio
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014349:Trypanosoma cruzi / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D052247:Nitric Oxide Synthase Type II