Impaired Innate Immunity in Tlr4−/− Mice but Preserved CD8+ T Cell Responses against Trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-Deficient Mice

PLoS Pathogens

Fanny Tzelepis¹  Bruna C. de Alencar¹  Maurício M. Rodrigues¹  Silvia Boscardin²  Marise P. Nunes³  Marcelo F. Santiago⁴  Fabieni S. Neves⁵  Raquel N. da Silva⁵  Maria Bellio⁵  Ana-Carolina Oliveira⁵  Gisele S. Cavalcanti⁵  Alberto Nóbrega⁵  Weberton Klezewsky⁵ 

[1]Centro Interdisciplinar de Terapia Gênica (CINTERGEN), Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil

[2]Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, São Paulo, Brazil

[3]Instituto Osvaldo Cruz (IOC/FIOCRUZ) Rio de Janeiro, Rio de Janeiro, Brazil

[4]Instituto de Biofísica Carlos Chagas Filho (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil

[5]Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil

关键词: Trypanosoma cruzi;    Parasitic diseases;    Cytotoxic T cells;    Toll-like receptors;    T cells;    Macrophages;    Trypomastigotes;    Immune response;   

DOI  :  10.1371/journal.ppat.1000870

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-γ secreting CD8+ T cells specific for H-2Kb-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-γ secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-γ+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-γ, TNF-α 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.

【 授权许可】

CC BY