Caspase-1/11 signalling is critical for inducing cytotoxic CD8+ T cells against Trypanosoma cruzi acute infection

PAROLI A; GONZALES PV; DIAZ LUJAN C; CANO R; GEA S

Congreso; Reunion Conjunta de Sociedades de Biociencias; 2017

Sociedades de Biociencias

NLRP3 inflammasome has been reported as a protection mechanism to control T. cruzi infection during the innate immune response. Once it gets assembled, active caspase-1 cleaves the pro- IL-1β and IL-18 cytokines into its active forms. We previously demonstrated that infected nlrp3-/- in a similar way to C57BL/6 WT mice, exhibited similar parasitemias associated with Th1 and Th17 phenotype. Furthermore, high levels of transaminases and pro-inflammatory cytokines IL-1β and IL-6 were found in plasma of WT and nlrp3-/- mice. Here, we studied the hepatic parasite load and its relation with the liver histopathological status from WT, nlrp3-/- and casp-1/11-/- mice. Additionally, we comparatively analyzed the expression of IL-1R and IL-18R on CD8+ T cells and the expansion of IFNγ-, IL-17- and IL-10-producing CD8+ T cells during acute T. cruzi infection. Male C57BL/6 WT, nlrp3-/- and casp1/11-/- mice were infected with T. cruzi (Tulahuén). The parasitic load was increased in both knock-out (KO) strains (p<0.001), presenting the casp1/11-/- mice the highest parasitism linked to a parasitemia peak at 21 dpi (p<0.05). Both KO strains presented minor hepatic leukocyte infltration (p<0.0001) with augmented F4/80+ (p<0.01) and reduced CD8+ T cell numbers (p<0.001) compared to WT mice. As expected, the number of IL1R+ (p<0.0001)and IL18R+ (p<0.001) CD8+ T lymphocytes was strongly diminished in casp1/11-/- mice. Interestingly, IL-17+CD8+ T cells were only present in WT mice (p<0.0001) while IFN-γ- and IL10+CD8+ cells were detected in WT and nlrp3-/- (p<0.001). Last, plasmatic IL-18 quantifcation revealed that casp1/11-/- animals were not capable of increasing its levels, unlike WT and nlrp3-/- mice. These results clearly show that although NLRP3 partially participates in the response against the parasite, casp-1/11 play a critical role in the induction of adaptive immunity mediated by cytotoxic CD8+ T cells although probably also contribute to tissue damage.