{"doi":"10.1371/journal.pntd.0009473","title":"Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro","abstract":"In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. 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 in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ 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 TBX21, EOMES and CXCL9 in response to IL-27. In vitro 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.","journal":"PLoS neglected tropical diseases","year":2021,"id":185452,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":741981,"name":"Todd Minning","orcid":"0000-0003-1331-9347","position":1,"is_corresponding":false},{"id":741982,"name":"María C. Albareda","orcid":"0000-0001-8256-8844","position":2,"is_corresponding":false},{"id":741983,"name":"Melisa D. Castro Eiro","orcid":"0000-0003-0780-8937","position":3,"is_corresponding":false},{"id":741984,"name":"M Alvarez","orcid":"0000-0003-4193-9148","position":4,"is_corresponding":false},{"id":742655,"name":"Bruno Lococo","orcid":null,"position":5,"is_corresponding":false},{"id":742656,"name":"Gonzalo César","orcid":null,"position":6,"is_corresponding":false},{"id":742657,"name":"Graciela Bertocchi","orcid":null,"position":7,"is_corresponding":false},{"id":742658,"name":"María J. Elias","orcid":null,"position":8,"is_corresponding":false},{"id":742659,"name":"María Belén Caputo","orcid":null,"position":9,"is_corresponding":false},{"id":343808,"name":"Rick L. Tarleton","orcid":"0000-0002-9589-5243","position":10,"is_corresponding":false},{"id":741985,"name":"Susana A. Laucella","orcid":"0000-0001-5224-5446","position":11,"is_corresponding":false},{"id":741980,"name":"María A. Natale","orcid":"0000-0001-5508-9266","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:48:38.805613Z","pmid":"34061845","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}