cruzi infection has previously been reported . When MDSCs were isolated and added to the cultures, the suppressive activity was partial, suggesting that other cells, likely regulatory T cells, might be also exerting the suppressive activity selleck screening library during the acute infection . Taking into account that mature macrophages (F4/80+) produce elevated levels of NO and that M-MDSCs
may express F4/80 marker [34, 35], our results revealed that about 20% of MDSCs co-express F4/80 (data not shown). In addition, a cross-talk between MDSCs and macrophages subverts type 1 toward type 2 immunity . Related to this, we previously observed a mixed Th1/Th2 profile in the BALB/c mice versus Th1 dominant response in B6 mice during parasitic infection [23,
37]. Our results indicate that infection with the Tulahuen strain of T. cruzi induced the recruitment of MDSCs subsets with different phenotypes. On the other hand, it has been demonstrated that cardiac M-MDSCs suppression is mainly mediated by NO and Arginase-1 during Y strain T. cruzi infection . Thus, MDSCs tissue localization, parasite strain, tropism, and virulence could be important factors for their better characterization. Various interesting studies have demonstrated that G-MDSCs may suppress CD8+ T cells by producing ROS that are triggered by an increased activation of STAT3 and NADPH oxidase [3, 27]. In agreement with this evidence, our results revealed an upregulation of NADPH oxidase and p-STAT3 in splenic MDSCs from infected BALB/c mice. In fact STAT3 not only prevents apoptosis but is also a crucial DZNeP Galeterone regulator of MDSCs expansion [38-40]. Many of the biological effects attributed to NO are actually mediated by peroxynitrites that are crucial mediators of MDSCs-mediated suppression. These peroxynitrites induce the nitration
of amino acids such as tyrosine, among others, and cause several alterations in T cells including the loss of TCR ζ-chain expression . Our results have shown that the percentage of splenic CD8+ T cells, which were nitrotyrosine positive, was substantially higher in infected BALB/c mice than in uninfected ones. Related to this, the nitration of tyrosine within the TCR/CD8 complex induced by MDSCs during cell–cell contact has been previously demonstrated in a tumor model . In agreement with the inhibition of IL-6 abrogating the accumulation of MDSCs in tumor-bearing mice , our data revealed a significant reduction of splenic MDSCs in IL-6KO versus wild-type mice, associated with a 100% mortality, thus suggesting the significance of IL-6 in the recruitment of MDSCs in order to maintain homeostasis during infection. The relevance of MDSCs in our model was evaluated by reduction assays using 5FU treatment. After treatment, a diminution of TN on CD8+ T cells was associated with elevated CD8+ cell activation, as measured by CD107a expression. In addition, IL-6 and IFN-γ were dramatically increased in plasma compared with untreated mice.