Adenosine regulates cytotoxic CD4 T lymphocytes in Trypanosoma cruzi infection

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

Congreso; 54th Annual Meeting; 2021

Chagas disease, a major public health problem in Latin America, is caused by the infection with the protozoan parasite Trypanosoma (T.) cruzi and has been spread to non-endemic regions by migratory movements. Chagas cardiomyopathy represents the most severe complication of the infection. Parasite persistence within the cardiac tissue is central to the etiology of the cardiomyopathy. The immune regulatory pathways that allow the chronic parasite persistence for such a long time remain mostly undefined. In recent years, the purinergic system has taken a robust significance as a central signaling pathway driving the outcome of the immune response. Expression of the CD39 and CD73 ectonucleotidases mediate the catabolism of extracellular ATP, which promotes pro-inflammatory responses, towards the anti-inflammatory mediator adenosine (ADO). We have reported that CD73-generated ADO dampens cardiac microbicidal responses and increases local T. cruzi load in acutely infected mice. Recently, a new CD4 T cell population with cytotoxic effector functions (CD4 CTL) has been reported. At steady state, CD4 CTL only resides in the intestine, whereas under inflammatory conditions, including viral infections, autoimmune disorders, and in response to tumor antigens, it expands in the peripheral blood and tissues. Their differentiation and participation in different adaptive immune responses, both beneficial and pathogenic, have not been completely understood yet. In the present work, we evaluated the role of ADO on the differentiation and functional capacity of the CD4 CTL population in T. cruzi infected mice.To this aim, we explored the effect of CD73 activity abrogation (CD73KO) on immune cells infiltrating target tissues during the acute phase of T. cruzi infection. We found that CD73KO cardiac tissue presented a higher frequency of CD4 T cells expressing the degranulation marker CD107a at 21 days post-infection (dpi), compared to the wild-type C57BL/6 (WT) counterpart (p