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-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.
Highlights
Chagas disease, the chronic cardiomyopathy caused by infection with the intracellular parasitic protozoan Trypanosoma cruzi, remains a major health problem in Central and South America [1]
Antibodies and IFN-c-producing effector T cells are essential for the immune control of infection by Trypanosoma cruzi, the intracellular protozoa that causes human Chagas disease
It is well established that innate sentinel cells sense T. cruzi through receptors for microbial structures, such as Toll-like receptors, it remained unclear whether endogenous inflammatory signals contribute to the development of adaptive immunity
Summary
The chronic cardiomyopathy caused by infection with the intracellular parasitic protozoan Trypanosoma cruzi, remains a major health problem in Central and South America [1]. While not excluding a secondary pathogenic role for autoimmunity, studies in humans and animal models support the concept that parasite persistence in myocardial tissues is the primary cause of chronic immunopathology [3,4,5,6]. Cohort studies with chagasic patients have linked chronic heart pathology to TH1-type responses [7], but this proposition was recently called into question by a report indicating that the frequency of IFN-c-producing effector/memory T cells is inversely correlated with the severity of chronic Chagas disease [8]. The dominant epitope specificities recognized by cytotoxic CD8 T cells are encoded by highly polymorphic genes [15], it is still unclear how T. cruzi escapes from immune surveillance [16,17,18]
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