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The decline of IFN-\u03b3-producing CD4<jats:sup>+<\/jats:sup>T cells in AIDS is a major contributing factor in reactivation of quiescent<jats:italic>Toxoplasma gondii<\/jats:italic>to an actively replicating stage of infection. Hence, it is important to characterize CD4-independent mechanisms that constrain acute<jats:italic>T. gondii<\/jats:italic>infection. We investigated the in vivo regulation of IFN-\u03b3 production by CD8<jats:sup>+<\/jats:sup>T cells, DN T cells and NK cells in response to acute<jats:italic>T. gondii<\/jats:italic>infection. Our data show that processing of IFN-\u03b3 by these non-CD4 cells is dependent on both IL-12 and IL-18 and the secretion of bioactive IL-18 in response to<jats:italic>T. gondii<\/jats:italic>requires the sensing of viable parasites by multiple redundant inflammasome sensors in multiple hematopoietic cell types. Importantly, our results show that expansion of CD8<jats:sup>+<\/jats:sup>T cells, DN T cells and NK cell by S4B6 IL-2 complex pre-treatment increases survival rates of mice infected with<jats:italic>T. gondii<\/jats:italic>and this is dependent on IL-12, IL-18 and IFN-\u03b3. Increased survival is accompanied by reduced pathology but is independent of expansion of T<jats:sub>Reg<\/jats:sub>cells or parasite burden. This provides evidence for a protective role of IL2C-mediated expansion of non-CD4 cells and may represent a promising lead to adjunct therapy for acute toxoplasmosis.<\/jats:p>","DOI":"10.1038\/s41598-020-70102-1","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T10:03:35Z","timestamp":1596535415000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Treatment of mice with S4B6 IL-2 complex prevents lethal toxoplasmosis via IL-12- and IL-18-dependent interferon-gamma production by non-CD4 immune cells"],"prefix":"10.1038","volume":"10","author":[{"given":"Andreas","family":"Kupz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saparna","family":"Pai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul R.","family":"Giacomin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Whan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8511-356X","authenticated-orcid":false,"given":"Pierre-Mehdi","family":"Hammoudi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7467-1451","authenticated-orcid":false,"given":"Nicholas C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine M.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,4]]},"reference":[{"key":"70102_CR1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7924.1","author":"F Seeber","year":"2016","unstructured":"Seeber, F. & Steinfelder, S. 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