Specific Treg cell depletion allows the emergence of parasite-specific CD8+ T cell immunity during Trypanosoma cruzi infection

C ARAUJO FURLAN; S BOCCARDO; C RODRIGUEZ; F FIOCCA VERNENGO; J TOSELLO BOARI; A GRUPPI; C MONTES; E ACOSTA RODRIGUEZ

Mar del Plata

Congreso; LXVI Reunión Anual de la Sociedad Argentina de Inmunología; 2018

Sociedad Argentina de Inmunología

Regulatory T cells CD4+Foxp3+ (Tregs) present dual roles during infections as they limit immunopathology but also restrain effector immune responses. During Trypanosoma cruzi (Tc) infection, Tregs role remain controversial. We previously demonstrated that after Tc infection, Tregs undergo a marked reduction in frequency at peripheral organs that was sustained over time. In the acute phase, Tregs became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. Additionally, the increase in Treg numbers by adoptive transfer experiments resulted in an impaired CD8 response accompanied by increased parasite levels. In order to further assess the biological relevance of the relative reduction in Tregs frequency during Tc infection, we evaluated here whether specific depletion of Tregs at different time points modulates the magnitude of effector responses, parasite burden and tissue damage. For this purpose, DEREG mice were infected with 5000 trypomastigotes and at days (d) 5 or 11 post-infection (pi) were injected with diphtheria toxin (DT) or PBS as control. A kinetic analysis revealed that while no differences were observed by DT-treatment at d11pi, mice injected at d5pi showed reduced parasite burden (p≤0.0006) and increased Tc-specific CD8+ T cells frequency and absolute numbers (p≤0.0098) in spleen and liver at d19pi, in comparison to PBS-injected counterparts. Furthermore, DT-treatment at d5pi also improved CD8 effector function, as shown by the increase in the frequency of splenic Tc-specific CD8+ cells able to degranulate (CD107a+) and produce IFN-gamma and/or TNF upon in vitro parasite stimulation in comparison to the control group (p≤0.0166). Finally, Tregs depletion at 5 or 11 dpi did not alter the activity of biochemical markers of tissue damage in comparison to PBS-treated mice. Our results suggest that limited response of activated Tregs during Tc infection is necessary for the emergence of protective anti-parasite CD8+ T cell immunity.