Early treg cell depletion promotes initial control of Trypanosoma Cruzi but leads to a deleterious outcome in the chronic phase during the experimental infection.

ARAUJO FURLÁN CL; BOCCARDO S; RODRIGUEZ C; MONTES CL; GRUPPI A; ACOSTA RODRIGUEZ EV

Congreso; Reunión Conjunta SAIC.SAI.SAFIS.; 2022

We reported that after Trypanosoma cruzi (Tc) infection, Tregsundergo a marked reduction in frequency. To assess its biologicalrelevance, we evaluated the effect of specific Tregs depletion onparasite control and the response of different immune cell populationsat different time points post-infection (pi). For this, DEREGmice were infected with Tc and injected with diphtheria toxin (DT)to eliminate Tregs or PBS as control at days (d) 5 and 6pi. At d7pi,DT treatment (Tx) showed a marginal effect on APC activation butincreased the numbers of splenic Tconv cells by d11pi, which displayedan activated/effector phenotype. At d20pi, DT Tx resulted inthe expansion of anti-parasite specific CD8+T cells in blood, spleenand liver, which was accompanied by reduced parasitemia levels.To investigate the Tregs suppressive mechanism operating, we focusedon CD39, a molecule highly upregulated by Tregs after infection.Thus, we transferred in vitro differentiated Tregs from WT orCD39KO mice to DT-treated mice. Mice that received WT Tregs butnot KO Tregs-transferred animals reverted at least in part the effectof Treg depletion, shown by numbers of total, Tconv and CD8+Tcells at d22pi in the spleen. Finally, we examined whether the Tregresponse in the acute phase had an effect over the chronic phase.At d100pi, DT Tx led to increased activity of plasmatic markers of tissuedamage as well as increased parasite burden in skeletal muscle(SM). Concomitantly, DT-treated mice showed decreased leucocyteinfiltrate but higher frequency of CD8+T cells in SM. Altogether, ourresults indicate that during Tc infection Tregs suppress CD8+T cellimmunity and impairs Tc control at the acute phase likely involvingthe modulation of APCs and Tconvs by a mechanism mediated byCD39 expression on Tregs. However, limiting the Treg response toachieve a better control of Tc replication in the acute phase doesnot necessarily improve parasite burden nor tissue damage in thechronic phase.