{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:40:44Z","timestamp":1775065244176,"version":"3.50.1"},"reference-count":121,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010336","name":"Hellman Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Toxoplasma gondii<\/jats:italic> induces a strong CD8 T cell response characterized by the secretion of IFN\u03b3 that promotes host survival during infection. The initiation of CD8 T cell IFN\u03b3 responses <jats:italic>in vitro<\/jats:italic> differs widely between clonal lineage strains of <jats:italic>T. gondii<\/jats:italic>, in which type I strains are low inducers, while types II and III strains are high inducers. We hypothesized this phenotype is due to a polymorphic \u201c<jats:underline>R<\/jats:underline>egulator <jats:underline>O<\/jats:underline>f <jats:underline>C<\/jats:underline>D8 <jats:underline>T<\/jats:underline> cell <jats:underline>R<\/jats:underline>esponse\u201d (ROCTR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Na\u00efve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe <jats:italic>Ifng<\/jats:italic> and produce IFN\u03b3 in response to <jats:italic>T. gondii<\/jats:italic> infected macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on <jats:italic>T. gondii<\/jats:italic> chromosomes (chr) VIIb-VIII, X and XII. These loci encompass multiple gene candidates highlighted by ROP16 (chrVIIb-VIII), GRA35 (chrX), TgNSM (chrX), and a pair of uncharacterized NTPases (chrXII), whose locus we report to be significantly truncated in the type I RH background. Although none of the chromosome X and XII candidates bore evidence for regulating CD8 T cell IFN\u03b3 responses, type I variants of ROP16 lowered <jats:italic>Ifng<\/jats:italic> transcription early after T cell activation. During our search for ROCTR, we also noted the parasitophorous vacuole membrane (PVM) targeting factor for dense granules (GRAs), GRA43, repressed the response suggesting PVM-associated GRAs are important for CD8 T cell activation. Furthermore, RIPK3 expression in macrophages was an absolute requirement for CD8 T cell IFN\u03b3 differentiation implicating the necroptosis pathway in T cell immunity to <jats:italic>T. gondii<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Collectively, our data suggest that while CD8 T cell IFN\u03b3 production to <jats:italic>T. gondii<\/jats:italic> strains vary dramatically, it is not controlled by a single polymorphism with strong effect. However, early in the differentiation process, polymorphisms in ROP16 can regulate commitment of responding CD8 T cells to IFN\u03b3 production which may have bearing on immunity to <jats:italic>T. gondii<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2023.1130965","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T04:47:31Z","timestamp":1684817251000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Variation in CD8 T cell IFN\u03b3 differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16"],"prefix":"10.3389","volume":"13","author":[{"given":"Angel K.","family":"Kongsomboonvech","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Garc\u00eda-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferdinand","family":"Njume","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott P.","family":"Souza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirk D. 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