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Here, we employed an attenuated uracil auxotroph strain of Type I\n              <jats:italic>Toxoplasma<\/jats:italic>\n              designated OMP to further untangle the early immune response to this parasitic pathogen. Experiments using \u03b1\u03b2 T cell-deficient\n              <jats:italic>Tcrb<\/jats:italic>\n              <jats:sup>\n                <jats:italic>-\/-<\/jats:italic>\n              <\/jats:sup>\n              mice unexpectedly revealed that an intact \u03b1\u03b2 T lymphocyte compartment was essential to survive infection with OMP. Subsequent antibody depletion and knockout mouse experiments demonstrated contributions from CD4\n              <jats:sup>+<\/jats:sup>\n              T cells and most predominantly CD8\n              <jats:sup>+<\/jats:sup>\n              T cells in resistance. Using transgenic knockout mice, we found only a partial requirement for IFN-\u03b3 and a lack of requirement for Toll-like receptor (TLR) adaptor MyD88 in resistance. In contrast to other studies on\n              <jats:italic>Toxoplasma<\/jats:italic>\n              , the ability to survive OMP infection did not require IL-12p40. Surprisingly, T cell-dependent IL-10 was found to be critical for survival, and deficiency of this cytokine triggered an abnormally high systemic inflammatory response. We also found that parasite molecule GRA24, a dense granule protein that triggers TLR-independent IL-12 production, acts as a virulence factor contributing to death of OMP-infected\n              <jats:italic>Tcrb<\/jats:italic>\n              <jats:sup>\n                <jats:italic>-\/-<\/jats:italic>\n              <\/jats:sup>\n              and\n              <jats:italic>IL-10<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice. Furthermore, resistance against OMP was restored in\n              <jats:italic>Tcrb<\/jats:italic>\n              <jats:sup>\n                <jats:italic>-\/-<\/jats:italic>\n              <\/jats:sup>\n              mice via monoclonal depletion of IL-12p40, suggesting that GRA24-induced IL-12 underlies the fatal immunopathology observed. Collectively, our studies provide insight into a novel and rapidly arising T lymphocyte-dependent anti-inflammatory response to\n              <jats:italic>T. gondii<\/jats:italic>\n              which operates independently of MyD88 and IL-12 and that depends on the function of parasite-dense granule protein GRA24.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                As a model infectious microbe and an important human pathogen, the apicomplexan\n                <jats:italic>Toxoplasma gondii<\/jats:italic>\n                has provided many important insights into innate and adaptive immunity to infection. We show here that a low virulence uracil auxotrophic\n                <jats:italic>Toxoplasma<\/jats:italic>\n                strain emerges as a virulent parasite in the absence of an intact T cell compartment. Both CD4\n                <jats:sup>+<\/jats:sup>\n                and CD8\n                <jats:sup>+<\/jats:sup>\n                T lymphocytes are required for optimal protection, in line with previous findings in other models of\n                <jats:italic>Toxoplasma<\/jats:italic>\n                infection. Nevertheless, several novel aspects of the response were identified in our study. Protection occurs independently of IL-12 and MyD88 and only partially requires IFN-\u03b3. This is noteworthy particularly because the cytokines IL-12 and IFN-\u03b3 have previously been regarded as essential for protective immunity to\n                <jats:italic>T. gondii<\/jats:italic>\n                . Instead, we identified the anti-inflammatory effects of T cell-dependent IL-10 as the critical factor enabling host survival. The parasite dense granule protein GRA24, a host-directed mitogen-activated protein kinase activator, was identified as a major virulence factor in T cell-deficient hosts. Collectively, our results provide new and unexpected insights into host resistance to\n                <jats:italic>Toxoplasma<\/jats:italic>\n                .\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01455-24","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:00:55Z","timestamp":1729688455000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["T lymphocyte-dependent IL-10 down-regulates a cytokine storm driven by\n            <i>Toxoplasma gondii<\/i>\n            GRA24"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-3258","authenticated-orcid":false,"given":"Claire M.","family":"Doherty","sequence":"first","affiliation":[{"name":"Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige R.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Emeanuwa","sequence":"additional","affiliation":[{"name":"Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Belmares Ortega","sequence":"additional","affiliation":[{"name":"Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara A.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8592-4733","authenticated-orcid":true,"given":"David J.","family":"Bzik","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-3327","authenticated-orcid":true,"given":"Eric Y.","family":"Denkers","sequence":"additional","affiliation":[{"name":"Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.4315\/0362-028X.JFP-11-417"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.05013-11"},{"key":"e_1_3_4_4_2","first-page":"1","volume-title":"The history and life-cycle of Toxoplasma gondii","author":"Dubey JP","year":"2013","unstructured":"Dubey JP. 2013. 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