Purinergic signaling modulates CD4+ T cells with cytotoxic potential during Trypanosoma cruzi infection

Abstract

Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation ofcardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linkedto ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, whichultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence ofT. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells andlinked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals thatHIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. Thefindings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting ofT. cruzi infection and have translational implications for therapy.