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 (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.