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.

Abstract

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-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 TH17 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.

• Authors: Ana Carolina Monteiro, Verônica Schmitz, Alexandre Morrot, Luciana Barros de Arruda, Fnu Nagajyothi, Alessandra Granato, João B Pesquero, Werner Müller-Esterl, Herbert B Tanowitz, Julio Scharfstein
• Journal: PLoS pathogens (PLoS Pathog) Vol. 3 Issue 11 Pg. e185 (Nov 2007) ISSN: 1553-7374 [Electronic] United States
• PMID: 18052532 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Kinins
• Receptor, Bradykinin B2
• Tumor Necrosis Factor-alpha
• Interleukin-12
• Interferon-gamma

Topics

• Adoptive Transfer
• Animals
• Chagas Disease (immunology, metabolism)
• Dendritic Cells (immunology, metabolism)
• Flow Cytometry
• Interferon-gamma (biosynthesis)
• Interleukin-12 (biosynthesis)
• Interleukin-17 (biosynthesis)
• Kinins (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Mutant Strains
• Polymerase Chain Reaction
• Receptor, Bradykinin B2 (immunology, metabolism)
• Th1 Cells (immunology, metabolism)
• Trypanosoma cruzi
• Tumor Necrosis Factor-alpha (biosynthesis)