ADENOSINE REGULATES CYTOTOXIC CD4 T LYMPHOCYTES IN TRYPANOSOMA CRUZI INFECTION

BERGERO, GASTÓN; MAZZOCO YANINA; EBERHARDT, NATALIA; AOKI, MARIA PILAR

Congreso; Reunión Anual de Sociedades de Biociencias; 2021

Growing evidence demonstrates a critical role of purinergic system in the modulation of the immune response and to determine the outcome of infections. Damaged cells release the pro-inflammatory molecule ATP, which is metabolized by the ectonucleotidases CD39 and CD73 to the anti-inflammatory mediator adenosine (ADO).The mechanisms involved in the induction of CD4 T cell population with cytotoxic effector functions (CD4 CTL) have not been evaluated in the setting of experimental T. cruzi infection. Here, we explored the effect of CD73 activity abrogation (CD73KO) on the differentiation and functional capacity of the CD4 CTL population in T. cruzi infected mice.Through flow cytometry, we found that expression of multiple effector molecules (granzyme B, perforin, IFN- and TNFα) and the degranulation marker, CD107a, were increased in CD4 T spleen cells of CD73KO mice compared to WT mice at 14 days post-infection (dpi) (p <0.05). Moreover, deficient CD4 cells exhibited higher cytotoxicity capacity evaluated by in vitro cytotoxicity model (% of dead cells WT vs KO: p<0,05).Furthermore, the frequency of CD4 CTL and their multifunctional capacity decreased when CD73-deficient cells were cultivated in an ADO-enriched medium (CD73KO vs CD73KO+ADO: p<0,05 ). As expected, when WT cells were cultivated in an ATP-enriched medium, to mimic CD73-deficient environment, an increase in the multifunctional capacity of CD4 CTL was observed (WT vs. WT+ATP: p<0.05) reaching similar levels as was observed for these populations in CD73KO cells. During acute (21dpi) and chronic (258 dpi) phase of the infection, the frequency of infiltrating CD4 CTL was higher in CD73KO cardiac tissue associated with diminished parasite burden (measured by real-time PCR), compared to the WT counterpart (p<0.05).These data suggest that CD73 activity and ADO balance frankly influence the functionality of CD4 CTL during the immune response against T. cruzi infection.