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

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

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

We reported that after Trypanosoma cruzi (Tc) infection, Tregs undergo a marked reduction in frequency. To assess its biological relevance, we evaluated the effect of specific Tregs depletion on parasite control and the response of different immune cell populations at different time points post-infection (pi). For this, DEREG mice 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 but increased the numbers of splenic Tconv cells by d11pi, which displayed an activated/effector phenotype. At d20pi, DT Tx resulted in the expansion of anti-parasite specific CD8+T cells in blood, spleen and liver, which was accompanied by reduced parasitemia levels. To investigate the Tregs suppressive mechanism operating, we focused on CD39, a molecule highly upregulated by Tregs after infection. Thus, we transferred in vitro differentiated Tregs from WT or CD39KO mice to DT-treated mice. Mice that received WT Tregs but not KO Tregs-transferred animals reverted at least in part the effect of Treg depletion, shown by numbers of total, Tconv and CD8+T cells at d22pi in the spleen. Finally, we examined whether the Treg response in the acute phase had an effect over the chronic phase. At d100pi, DT Tx led to increased activity of plasmatic markers of tissue damage as well as increased parasite burden in skeletal muscle (SM). Concomitantly, DT-treated mice showed decreased leucocyte infiltrate but higher frequency of CD8+T cells in SM. Altogether, our results indicate that during Tc infection Tregs suppress CD8+T cell immunity and impairs Tc control at the acute phase likely involving the modulation of APCs and Tconvs by a mechanism mediated by CD39 expression on Tregs. However, limiting the Treg response to achieve a better control of Tc replication in the acute phase does not necessarily improve parasite burden nor tissue damage in the chronic phase.