Reduced frequency of activated Foxp3+ regulatory T cells allows the emergence of specific CD8+ T cell immunity during T. cruzi infection

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

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

CD4+ Foxp3+ T cells (Tregs) present a dual role in infections as they limit immunopathology but also restrain immunity to the pathogen. During T. cruzi (Tc) infection Tregs response has been poorly characterized. We previously determined that during this infection, Tregs become activated, upregulate a wide range of suppressive markers and acquire a transcriptional program specialized in controlling Th1 responses. However, Tregs frequency is significantly reduced in the periphery of infected mice as a result of a low proliferation rate and impaired induction of peripheral Tregs.Here, our aim was to assess the biological relevance of reduced Tregs frequency in Tc infection. First, we adoptively transferred Tregs generated in vitro from naïve CD4 T cells cultured with IL-2, TFG-beta and all-trans retinoic acid. Injection was performed at day (d) 11 post-infection (pi) in WT mice. At d17pi, Tregs recipient mice showed increased parasite burden in blood, spleen and liver concomitantly with decreased frequency and numbers of total and Tc-specific CD8 T cells compared to non-transferred animals. No differences were observed between the two groups in the levels of biochemical damage markers. As a second approach, Tregs were specifically depleted by the injection of diphtheria toxin (DT) in DEREG mice at d5pi. Significantly reduced Tc levels and augmented parasite specific CD8 response were observed in spleen and liver of DT-treated DEREG mice in comparison to PBS-injected counterparts at d19pi. CD8 functionality was also improved by Tregs depletion, as shown by the significant increase in the frequency of splenic specific CD8 cells able to degranulate (CD107a+) and produce IFN-gamma and TNF upon parasite-specific stimulation in DT-treated DEREG mice. These results outstand Tregs role during acute Tc infection, suggesting that a reduction in activated Tregs frequency may be necessary to allow the development of the CD8 T cell immunity responsible of parasite control.