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

ARAUJO FURLÁN CL; FIOCCA VERNENGO F; MONTES CL; RODRIGUEZ C; GRUPPI A; BOCCARDO S; TOSELLO BOARI J; ACOSTA RODRIGUEZ EV

Congreso; SAIC-SAI-SAFIS 2018.; 2018

Regulatory T cells CD4+Foxp3+ (Tregs) present dual roles duringinfections as they limit immunopathology but also restrain effectorimmune responses. During Trypanosoma cruzi (Tc) infection, Tregsrole remain controversial. We previously demonstrated that after Tcinfection, Tregs undergo a marked reduction in frequency at peripheralorgans that was sustained over time. In the acute phase, Tregsbecame activated and acquired a phenotypic and transcriptionalprofile consistent with suppression of type 1 inflammatory responses.Additionally, the increase in Treg numbers by adoptive transferexperiments resulted in an impaired CD8 response accompaniedby increased parasite levels. In order to further assess the biologicalrelevance of the relative reduction in Tregs frequency during Tcinfection, we evaluated here whether specific depletion of Tregs atdifferent time points modulates the magnitude of effector responses,parasite burden and tissue damage. For this purpose, DEREG micewere infected with 5000 trypomastigotes and at days (d) 5 or 11post-infection (pi) were injected with diphtheria toxin (DT) or PBSas control. A kinetic analysis revealed that while no differences wereobserved by DT-treatment at d11pi, mice injected at d5pi showed reducedparasite burden (p≤0.0006) and increased Tc-specific CD8+T cells frequency and absolute numbers (p≤0.0098) in spleen andliver at d19pi, in comparison to PBS-injected counterparts. Furthermore,DT-treatment at d5pi also improved CD8 effector function, asshown 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 controlgroup (p≤0.0166). Finally, Tregs depletion at 5 or 11 dpi did not alterthe activity of biochemical markers of tissue damage in comparisonto PBS-treated mice. Our results suggest that limited response ofactivated Tregs during Tc infection is necessary for the emergenceof protective anti-parasite CD8+ T cell immunity.