: Trypanosoma cruzi Promotes In vivo and In vitro the Secretion of IL-10 by Dendritic Cells:

PINO MARTINEZ AGUSTINA M.; PONCINI CAROLINA V.; SOLANA MARIA E; DUFFY TOMAS; SCHIJMAN ALEJANDRO G. ; GONZALEZ CAPPA STELLA M; ALBA SOTO CATALINA D.

Lugano

Simposio; 11th International Symposium on Dendritic Cells in Fundamental and Clinical Immunology DC2010:; 2010

Swiss Vaccine Research Institute

Trypanosoma cruzi Promotes In vivo and In vitro the Secretion of IL-10 by Dendritic Cells: Consequences on the Induction of Protective Immunity.   Trypanosoma cruzi (T. cruzi) is a complex protozoan parasite with intra and extra cellular stages that causes persistent infection in the mammalian hosts. We demonstrated previously that T. cruzi down-modulates the expression of MHC class II and costimulatory molecules as well as impairs the T-cell stimulatory capacity of dendritic cells (DC) in vivo and in vitro (Alba-Soto et al., 2003; Poncini et al,2008; Infection and Immunity). In vitro interaction of T. cruzi trypomastigotes with bone-marrow derived DC stimulated with LPS increases the gap between IL-10 and IL-12 p70 production by DC. Neutralization of IL-10 produced by DC partially reverts this parasite-driven functional impairment. The priming of IL-10 during infection with intracellular pathogens is associated with pathogen persistence and increased infectivity. As exogenous and autocrine IL-10 disminishes the capacity of DC to activate and sustain inflammatory immune responses, parasitic induction of IL-10 by DC might play a major role in the parasite-driven immune modulation. Here, we analyzed the production of IL-10 and the expression of maturation markers by DC populations residing in secondary lymphoid organs during experimental murine infection with T. cruzi. We followed the kinetics of parasite burden in secondary lymphoid organs (spleen and afferent lymph node)by Real Time-PCR. The local increase of the parasite load is accompanied by the down-modulation of MHC II expression and the rise of intracellular IL-10 levels by semimature (CD11cint) DC populations residing in these organs. Furthermore, as two different T. cruzi strains with polar behavior were used for infection, we concluded that parasite-induced DC modulation was related to the duplication time and not to the virulence of the parasite strain. Next, we evaluated the impact of parasite-induced autocrine IL-10 on the stimulation of anti-parasite immune responses by DC in a model of DC based vaccination. DC from wild-type mice secreted high amounts of IL-10 and were poorly immunogenic when pulsed in vitro with trypomastigote lysate. Conversely, DC from IL-10-deficient mice pulsed with the same trypomastigote lysate secreted increased amounts of Th1-related cytokines (IL-12, TNF-¦Á) and stimulated higher allogeneic and antigen-specific lymphocyte responses than their wild-type counterparts. Furthermore, following adoptive transfer, all wild-type mice immunized with antigen-pulsed IL-10-deficient DC cells survived to a lethal challenge with T. cruzi. Efficient immunity was associated with the activation of endogenous DC and antigen-specific IFN-¦Ã and IL-10 production by lymphocytes of immunized mice. These results emphasize the negative impact of parasite-induced autocrine IL-10 on DC function and provide in vivo evidence of this immuno modulatory mechanism of T. cruzi. The successful DC-based vaccination against the parasite supports the role of IL-10 secreted by sensitizing DC in the down-modulation of protective immune responses. Strategies leading to blockade of IL-10 released by DC during the early induction of immune responses could enhance the effectiveness of vaccine formulations. Funded by CONICET, ANPCyT, Fundaci¨®n Bunge y Born and UBACYT.   - INFECTIOUS DISEASES,Mouse models,Cytokines and chemokines,Dynamics of immune response,Parasites