Myeloid-derived suppressor cells are key players to counter exacerbated inflammatory response during acute Trypanosoma cruzi infection

AROCENA A; ONOFRIO L; PAROLI A; CANO RC; AOKI MP; GEA S

Congreso; International Congress of Immunology; 2013

Myeloid-derived suppressor cells (MDSC), CD11b+Gr1+, are main players of the immune suppressive network. Previously, we reported that during acute infection with the causative agent of Chagas disease, Trypanosoma cruzi,  BALB/c mice showed a lesser inflammatory response and improved survival than B6 mice which developed severe inflammation and pathology. Recent studies have demonstrated the MDSC presence in this scenario although the suppressor mechanisms have not been fully explored. In this study we demonstrated a higher increase of CD11b+Gr1+ cells in spleen and liver of infected BALB/c compared to B6 mice.  The phenotypic analysis of MDSC subsets revealed a greater number of granulocytic cells (CD11b+LY6G+LY6Clow) in spleen from BALB/c respect to B6 mice, whereas monocytic population (CD11b+LY6G?LY6Chigh) was the predominant subset in the liver of both strains. Notably, splenic MDSC from infected BALB/c inhibited the ConA induced splenocyte proliferative response. The treatment with inhibitor of reactive oxygen species (NAC) or inhibitor of nitric oxide synthase (L-NMMA) restored the proliferative response. In addition, an up-regulation of NADPH oxidase p47 phox subunit and p-STAT3 occurred in MDSC. A higher number of infected CD8+ T-cells suffered TCR nitration compared to uninfected controls. Infected IL-6 deficient mice showed less recruitment of MDSC and impaired survival. Remarkably, the in vivo depletion of MDSC by 5FU led to an increased production of IL-6, IFNã and Th17 response with increased parasitemia and mortality. In summary, our data show for the first time the mechanisms of MDSC displayed as crucial regulators of T. cruzi infection induced inflammation. .