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IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether <jats:italic>in vitro<\/jats:italic> treatment with IL-27 and IL-7 might improve <jats:italic>T<\/jats:italic>. <jats:italic>cruzi<\/jats:italic>-specific polyfunctional T-cell responses. <jats:italic>In vitro<\/jats:italic> exposure of PBMCs to <jats:italic>T<\/jats:italic>. <jats:italic>cruzi<\/jats:italic> induced a downregulation of IL-27R in CD4<jats:sup>+<\/jats:sup> T cells and an upregulation in CD8<jats:sup>+<\/jats:sup> T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes <jats:italic>TBX21<\/jats:italic>, <jats:italic>EOMES<\/jats:italic> and <jats:italic>CXCL9<\/jats:italic> in response to IL-27. <jats:italic>In vitro<\/jats:italic> treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27\/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009473","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T20:36:42Z","timestamp":1622579802000},"page":"e0009473","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5508-9266","authenticated-orcid":true,"given":"Mar\u00eda Ail\u00e9n","family":"Natale","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1331-9347","authenticated-orcid":true,"given":"Todd","family":"Minning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-8844","authenticated-orcid":true,"given":"Mar\u00eda Cecilia","family":"Albareda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0780-8937","authenticated-orcid":true,"given":"Melisa Daiana","family":"Castro Eiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4193-9148","authenticated-orcid":true,"given":"Mar\u00eda Gabriela","family":"\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Lococo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Cesar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Bertocchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9121-4781","authenticated-orcid":true,"given":"Mar\u00eda Josefina","family":"Elias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Bel\u00e9n","family":"Caputo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick Lee","family":"Tarleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-5446","authenticated-orcid":true,"given":"Susana Adriana","family":"Laucella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"pntd.0009473.ref001","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1001\/jama.298.18.2171","article-title":"Evaluation and treatment of Chagas disease in the United States: A systematic review","volume":"298","author":"C Bern","year":"2007","journal-title":"J Am Med Assoc"},{"key":"pntd.0009473.ref002","unstructured":"WHO. 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