Immunoendocrine dysbalance during uncontrolled T. cruzi infection is associated with the acquisition of a Th-1-like phenotype by Foxp3(+) T cells

González, Florencia B.; Villar, Silvina R.; Fernández Bussy, Rodrigo; Martin, Gaëlle H.; Pérol, Louis; Manarin, Romina; Spinelli, Silvana V.; Pilon, Caroline; Cohen, José Laurent; Bottasso, Oscar A.; Piaggio, Eliane; Pérez, Ana R.

We previously showed that Trypanosomacruzi infection in C57BL/6 mice results in a lethal infection linked to unbalanced pro- and anti-inflammatory mediators production. Here, we examined the dynamics of CD4(+)Foxp3(+) regulatory T (Treg) cells within this inflammatory and highly Th1-polarized environment. Treg cells showed a reduced proliferation rate and their frequency is progressively reduced along infection compared to effector T (Teff) cells. Also, a higher fraction of Treg cells showed a naïve phenotype, meanwhile Teff cells were mostly of the effector memory type. T. cruzi infection was associated with the production of pro- and anti-inflammatory cytokines, notably IL-27p28, and with the induction of T-bet and IFN-γ expression in Treg cells. Furthermore, endogenous glucocorticoids released in response to T. cruzi-driven immune activation were crucial to sustain the Treg/Teff cell balance. Notably, IL-2 plus dexamethasone combined treatment before infection was associated with increased Treg cell proliferation and expression of GATA-3, IL-4 and IL-10, and increased mice survival time. Overall, our results indicate that therapies aimed at specifically boosting Treg cells, which during T. cruzi infection are overwhelmed by the effector immune response, represent new opportunities for the treatment of Chagas disease, which is actually only based on parasite-targeted chemotherapy.