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Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of  Trypanosoma cruzi  through the triggering of G-protein-coupled bradykinin B 2  receptors (B 2 R). Here we report that C57BL/6.B 2 R −/−  mice infected intraperitoneally with  T. cruzi  display higher parasitemia and mortality rates as compared to B 2 R +/+  mice. qRT-PCR revealed a 5-fold increase in  T. cruzi  DNA (14 d post-infection [p.i.]) in B 2 R −/−  heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-γ-producing CD4 +  and CD8 +  T cells in the spleen of B 2 R −/−  and wild-type mice. However, production of IFN-γ by effector T cells isolated from B 2 R −/−  heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-γ-producing (CD4 + CD44 +  and CD8 + CD44 + ) T cells both in the spleen and heart while B 2 R −/−  mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B 2 R −/−  mice was linked to upregulated secretion of IL-17 and TNF-α by antigen-responsive CD4 +  T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c +  DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B 2 R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c +  DCs isolated from B 2 R +/+  spleen, but not by DCs from B 2 R −/−  mice. Notably, adoptive transfer of B 2 R +/+  CD11c +  DCs (intravenously) into B 2 R −/−  mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed T H 17 responses. Collectively, our results demonstrate that activation of B 2 R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to  T. cruzi  infection.

plos pathogens

Bradykinin B2 Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses