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

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 (B2R). Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R(+/+) mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.])in B2R(-/-) 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-gamma-producing CD4(+) and CD8(+) T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild- type mice. As the infection continued, wild- type mice presented IFN-gamma-producing (CD4(+)CD44(+)and CD8(+)CD44(+)) T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R(-/-) mice was linked to upregulated secretion of IL-17 and TNF-alpha 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/B2R pathway. Further, systemic injection of trypomastigotes induced IL- 12 production by CD11c(+) DCs isolated from B2R+/+ spleen, but not by DCs from B2R(-/-) mice. Notably, adoptive transfer of B2R(+-/+-) CD11c(+) DCs (intravenously) into B2R-/- 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 B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection.