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However, little is known about the mechanisms leading to functional differentiation of this T cell subset in this model. In the current work, we investigated the possibility that the IL-18\/MyD88 pathway is central for the generation of effector \u03b3\u03b4 T cells, playing a role for resistance against infection. We found that splenic \u03b3\u03b4+CD3+ cells were rapidly expanded (10\u201314 days post infection), which was accompanied by an early \u03b3\u03b4 T cell infiltration into the heart. In the following days, intracardiac parasitism was reduced, the protective immunity being accompanied by decreased \u03b3\u03b4 T cells tissue infiltration. As predicted, there was a drastic reduction of \u03b3\u03b4 T cells in Myd88- and Il18r1-deficient mice, both transgenic strains displaying a susceptible phenotype with increased intracardiac parasitism. In vivo and in vitro assays confirmed that IL-18R deficiency hampered \u03b3\u03b4 T cell proliferation. Further characterization revealed that T. cruzi infection up-regulates IL-18R expression in WT \u03b3\u03b4+ T cell population whereas Il18r1\u2212\/\u2212 mice showed impaired generation of cytotoxic GzB+ and IFN-\u03b3-producing \u03b3\u03b4 T cells. Consistently, in vitro cytotoxicity assay confirmed that cytolytic function was impaired in Il18r1-deficient \u03b3\u03b4 T cells. As a proof of concept, adoptive transfer of WT \u03b3\u03b4 T cells rescues Il18r1-deficient mice from susceptibility, reducing parasitemia and abrogating the mortality. Collectively, our findings implicate the IL-18R-MyD88 signaling in the mechanisms underlying generation of immunoprotective \u03b3\u03b4 T cells response in experimental Trypanosoma cruzi infection.<\/jats:p>","DOI":"10.1002\/jlb.4ma0420-568r","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T22:26:13Z","timestamp":1590445573000},"page":"1239-1251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["IL-18R signaling is required for \u03b3\u03b4 T cell response and confers resistance to <i>Trypanosoma cruzi<\/i> infection"],"prefix":"10.1093","volume":"108","author":[{"given":"Julia Barbalho","family":"da Mota","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Imunologia Celular e Molecular, Instituto de Biof\u00edsica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0725-0198","authenticated-orcid":true,"given":"Juliana","family":"Echevarria-Lima","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunologia B\u00e1sica e Aplicada, Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda","family":"Kyle-Cezar","sequence":"additional","affiliation":[{"name":"Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King\u2019s College London , London , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matheus","family":"Melo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunologia Celular e Molecular, Instituto de Biof\u00edsica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-2740","authenticated-orcid":true,"given":"Maria","family":"Bellio","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunobiologia, Departamento de Imunologia, Instituto de Microbiologia Paulo de G\u00f3es, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7510-7625","authenticated-orcid":true,"given":"Julio","family":"Scharfstein","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunologia Celular e Molecular, Instituto de Biof\u00edsica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0036-3720","authenticated-orcid":true,"given":"Ana 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