{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:51:59Z","timestamp":1789051919040,"version":"build-2803163510"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"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>Chagas disease (CD) is a neglected chronic infection caused by the protozoan parasite<jats:italic>Trypanosoma cruzi<\/jats:italic>(<jats:italic>T. cruzi<\/jats:italic>). A significant portion of infected people develops cardiac or digestive alterations over a lifetime. Since several chronic infections associated with antigen persistence and inflammation have been shown to lead to T cell exhaustion, new therapies targeting co-inhibitory receptors to regain T cell activity are under consideration. This study explored immune therapeutic approaches targeting the inhibitory PD-1\/PD-L pathway in an experimental model for CD. Infected PD-L1 knockout mice (PD-L1 KO) showed increased systemic parasitemia in blood although no significant differences in parasite load were observed in different organs. Furthermore, we found no significant differences in the frequency of activated T cells or proinflammatory cytokine production when compared to WT counterparts. PD-L1 deficiency led to the production of IL-10 by CD8<jats:sup>+<\/jats:sup>T cells and an upregulation of Tim-3 and CD244 (2B4). Unexpectedly, the lack of PD-L1 did not contribute to a significantly improved T cell response to infection. Single blockade and combined blockade of PD-1 and Tim-3 using monoclonal antibodies confirmed the results observed in infected. PD-L1 KO mice. Our results describe for the first time that the interruption of the PD-1\/PD-L1 axis during acute<jats:italic>T. cruzi<\/jats:italic>infection does not necessarily enhance the immune response against this parasite. Its interruption favors increased levels of parasitemia and sustained upregulation of other co-inhibitory receptors as well as the production of regulatory cytokines. These results suggest that the clinical application of immune therapeutic approaches targeting the<jats:italic>PD-1\/PD-L1<\/jats:italic>axis in CD might be risky and associated with adverse events. It highlights that more research is urgently needed to better understand the immune regulation of T\u00a0cells in CD before designing immune therapeutic approaches for a clinical context.<\/jats:p>","DOI":"10.3389\/fimmu.2022.866120","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T06:39:41Z","timestamp":1655966381000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of the PD-1\/PD-L1 Pathway in Experimental Trypanosoma cruzi Infection and Potential Therapeutic Options"],"prefix":"10.3389","volume":"13","author":[{"given":"Yanina","family":"Arana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Isela","family":"G\u00e1lvez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"B1","first-page":"33","article-title":"Chagas Disease in Latin America: An Epidemiological Update Based on 2010 Estimates","volume":"90","year":"2015","journal-title":"Wkly Epidemiol Rec (WER)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1602095","article-title":"Antiparasitic Treatment Induces an Improved CD8(+) T Cell Response in Chronic Chagasic Patients","volume":"198","author":"Mateus","year":"2017","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.hgmx.2016.09.010","article-title":"Chagas Disease: Current Perspectives on a Forgotten Disease","volume":"81","author":"\u00c1lvarez-Hern\u00e1ndez","year":"2018","journal-title":"Rev M\u00e9d Hosp Gen M\u00e9xico"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1590\/S0074-02762009000900027","article-title":"Cellular and Genetic Mechanisms Involved in the Generation of Protective and Pathogenic Immune Responses in Human Chagas Disease","volume":"104","author":"Dutra","year":"2009","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01047-10","article-title":"Regulation of Trypanosoma Cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1","volume":"79","author":"Gutierrez","year":"2011","journal-title":"Infect Immun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000688","article-title":"Chagas Cardiomyopathy in the Context of the Chronic Disease Transition","volume":"4","author":"Hidron","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12107","article-title":"Immunoregulatory Networks in Human Chagas Disease","volume":"36","author":"Dutra","year":"2014","journal-title":"Parasit Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00997","article-title":"Programmed Cell Death Protein 1-PDL1 Interaction Prevents Heart Damage in Chronic Trypanosoma Cruzi Infection","volume":"9","author":"Fonseca","year":"2018","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1590\/S0100-879X2011007500005","article-title":"Evasion of Immune Responses by Trypanosoma Cruzi, the Etiological Agent of Chagas Disease","volume":"44","author":"DosReis","year":"2011","journal-title":"Braz J Med Biol Res"},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.141.1.289","article-title":"Novel Mechanism for Trypanosoma Cruzi-Induced Suppression of Human Lymphocytes. 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