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

PLoS Pathogens

Herbert B Tanowitz¹  Fnu Nagajyothi¹  João B Pesquero²  Werner Müller-Esterl³  Verônica Schmitz⁴  Ana Carolina Monteiro⁴  Alessandra Granato⁴  Julio Scharfstein⁴  Luciana Barros de Arruda⁵  Alexandre Morrot⁶ 

[1]Albert Einstein College of Medicine, Bronx, New York, United States of America

[2]Departmento de Biofisica, USP, São Paulo, Brazil

[3]Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany

[4]Instituto de Biofisica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil

[5]Instituto de Microbiologia Paulo de Goes, UFRJ, Rio de Janeiro, Brazil

[6]Intracellular Parasite Biology Section Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America

关键词: T cells;    Trypanosoma cruzi;    Cytotoxic T cells;    Spleen;    Parasitic diseases;    Heart;    Test statistics;    Mouse models;   

DOI  :  10.1371/journal.ppat.0030185

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 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-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 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.

【 授权许可】

CC BY