Characterization of the tolerogenic potential of T. cruzi-differentiated dendritic cells.

PONCINI CAROLINA V.; BATALLA ESTELA; ALBA SOTO CATALINA D.; GONZALEZ-CAPPA STELLA MARIS

CABA

Congreso; First French - Argentine Immunology Congress. LVIII Reunión Anual de la Sociedad Argentina de Inmunología.; 2010

French Society of Immunology and Sociedad Argentina de Inmunología

 Recently, we have demonstrated the ability of trypomastigotes (Tp) to modulate the differentiation stage and functionality of bone marrow-derived dendritic cells (DC) to a regulatory phenotype in vitro. Tp fail to activate DC and modulate LPS activation. DC display tolerogenic properties: they produce high levels of IL-10, less IL-12 and induce a poor alloresponse. In addition, we have demonstrated that both live and heat-killed Tp (Tphk) induce the regulatory phenotype in DC, characterized by an alternative activation state with enhanced ERK1/2 and STAT3 phosphorylation during LPS-stimulation. MEK inhibition led to a reduced production of IL-10 (p<0.001) and a total reversion of the impaired capacity to induce a non-related antigen-specific response (p<0.01). In order to characterize other signaling pathways associated with IL-10 induction, we treated DC with specific pharmacologic inhibitors. Inhibition of NF-kappaB abrogated Tp+LPS-induced IL-10 production, but inhibition of STAT3 did not. The modulation of antigen presenting cells functionality as an evasion mechanism is a common strategy displayed by pathogens. To determine the role and the regulatory potential of DC differentiated in the presence of Tphk plus LPS with or without MEK inhibitor (DCi or DCreg) in vivo, we transferred these cells into syngeneic naive mice. Five days later, mice were challenged with a lethal dose of Tp. Preliminary results show that both types of DC apparently mediated the induction of a protective anti-parasitic response. Transferred mice exhibit lower counts of bloodstream forms, more pronounced in mice transferred with DCi. In addition, all DC recipient mice survived to the lethal challenge with T. cruzi after 35 days post-infection. In conclusion, these results suggest a possible protective role for regulatory DC during infection in vivo, though further studies are needed in order to unravel the role of immunoregulatory mechanisms during T. cruzi infection.