Purinergic signaling modulates CD4+ T cells with cytotoxic potential during Trypanosoma cruzi infection
Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki
Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki
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Research Article Immunology Infectious disease Inflammation

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

Authors

Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki

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Figure 6

T.cruzi infection expands a CD39+CD73–P2X7+ CD4+ T cell population.

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T.cruzi infection expands a CD39+CD73–P2X7+ CD4+ T cell population. (A)...
(A) Representative contour plots and quantification of CD39 and CD73 expression in splenic CD4+ T cells at the indicated time points after infection (n = 5 per time). (B and C) CD4+ T cells were TCR-stimulated in the presence of neutralizing anti–IFN-γ (40 μg/mL) or anti–IL-6 (5 μg/mL) antibodies, recombinant IL-6 (10 pg/mL), or isotype control. MFI of CD39 (B) and CD73 (C) was evaluated at 72 hours after activation by flow cytometry. (D) P2X7 expression in splenic CD4+ T cells at the indicated time points. (E) Kinetics of effector memory (CD44+CD62L–), central memory (CD44+CD62L+), and naive (CD44–CD62L+) CD4+ T cell population frequency at the indicated time points after infection. (F) Frequency (top) and MFIs (bottom) of CD39 and CD73 expression in effector, memory, and naive CD4+ T cell populations. (G) Kinetics of CD39 and CD73 expression in cardiac CD45+CD3+CD4+ cells displayed as frequency (top) and MFIs (bottom). Two-way ANOVA followed by Tukey’s post hoc test was performed to compare frequencies in A–G (*CD39+ vs. CD73+, #CD39+ vs. CD39+CD73+, §CD73+ vs. CD39+CD73+; P < 0.05) (*effector vs. memory, #effector vs. naive, §memory vs. naive; P < 0.05). Independent t tests were performed to compare each time point with the previous one. One-way ANOVA followed by Tukey’s post hoc test was conducted for B and C. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.