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 B₂ 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-γ-producing CD4⁺ and CD8 ⁺ T cells in the spleen of B₂R^-/- and wild-type mice. However, production of IFN-γ 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-γ-producing (CD4⁺CD44⁺ and CD8 ⁺CD44⁺) T cells both in the spleen and heart while B ₂R^-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B ₂R^-/- 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/B₂R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c⁺ DCs isolated from B ₂R^+/+ 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_H17 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.