{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:12:07Z","timestamp":1778562727037,"version":"3.51.4"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chagas disease, caused by\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    , is the major cause of infectious cardiopathology worldwide. Although cytotoxic CD4 T-cells (CD4 CTLs) have recently been recognized as crucial effectors in infections and inflammation, the mechanisms that control their differentiation and impact on pathological outcomes remain largely undefined. Here, we demonstrate that the ectonucleotidase CD73, which generates adenosine from extracellular AMP, acts as a key immunoregulator of CD4 CTL response during\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    infection. Using murine models, we found that infection induced a robust expansion of CD4 T-cells expressing granzyme B, perforin, and IFN-\u03b3. CD73 deficiency improved parasite control and amplified the frequency and cytotoxic program of CD4 T-cells during the acute phase. However, the absence of CD73 also led to sustained cardiac inflammation, extensive fibrosis, and impaired contractility during chronic infection. In patients with asymptomatic chronic Chagas disease, circulating CD4 T-cells exhibited elevated granzyme B expression, predominantly within the CD73\n                    <jats:sup>-<\/jats:sup>\n                    subset. Consistently, cardiac tissue from patients with chronic terminal Chagas cardiomyopathy showed transcriptomic enrichment of granzyme B (\n                    <jats:italic>GZMB<\/jats:italic>\n                    ), perforin (\n                    <jats:italic>PRF1<\/jats:italic>\n                    ), and IFN-\u03b3 (\n                    <jats:italic>IFNG<\/jats:italic>\n                    ), with CD4 T-cells as the major contributors. Together, these findings identify CD73 ectoenzyme as a critical immunometabolic checkpoint that modulates CD4 CTL responses, revealing a dual role for this pathway in controlling infection and limiting tissue damage.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1770276","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T04:30:04Z","timestamp":1778560204000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD73 activity controls cytotoxic CD4 T-cell response driving myocardial pathology in chronic Chagas disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Gast\u00f3n","family":"Bergero","sequence":"first","affiliation":[{"name":"Universidad Nacional de C\u00f3rdoba, Facultad de Ciencias Qu\u00edmicas, Departamento de Bioqu\u00edmica Cl\u00ednica","place":["C\u00f3rdoba, Argentina"]},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y 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de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Centro de Investigaci\u00f3n en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda (CIBICI)","place":["C\u00f3rdoba, Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Rivarola","sequence":"additional","affiliation":[{"name":"Universidad Nacional de C\u00f3rdoba, Facultad de Ciencias M\u00e9dicas, Centro de Investigaci\u00f3n de la Enfermedad de Chagas y Leishmaniasis","place":["C\u00f3rdoba, Argentina"]},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Instituto de Investigaciones en Ciencias de la Salud (INICSA)","place":["C\u00f3rdoba, Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Del Rosso","sequence":"additional","affiliation":[{"name":"Universidad Nacional de C\u00f3rdoba, Facultad de Ciencias Qu\u00edmicas, Departamento de Bioqu\u00edmica Cl\u00ednica","place":["C\u00f3rdoba, Argentina"]},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Centro de Investigaci\u00f3n en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda (CIBICI)","place":["C\u00f3rdoba, Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria P.","family":"Aoki","sequence":"additional","affiliation":[{"name":"Universidad Nacional de C\u00f3rdoba, Facultad de Ciencias Qu\u00edmicas, Departamento de Bioqu\u00edmica Cl\u00ednica","place":["C\u00f3rdoba, Argentina"]},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Centro de Investigaci\u00f3n en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda (CIBICI)","place":["C\u00f3rdoba, Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3201\/eid3109.241700","article-title":"Chagas disease, an endemic disease in 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