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Flow cytometric analysis of PBMCs from patients with either <jats:italic>P. falciparum<\/jats:italic> or <jats:italic>P. knowlesi<\/jats:italic> malaria revealed a pronounced population of CD4<jats:sup>+<\/jats:sup> T cells co\u2010expressing very high levels of CD4 and CD38 we have termed CD4<jats:sup>hi<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> T cells. We set out to gain insight into the function of these novel cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CD4<jats:sup>+<\/jats:sup> T cells from 18 patients with <jats:italic>P. falciparum<\/jats:italic> or <jats:italic>P. knowlesi<\/jats:italic> malaria were assessed by flow cytometry and sorted into populations of CD4<jats:sup>hi<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> or CD4<jats:sup>norm<\/jats:sup> T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD4<jats:sup>hi<\/jats:sup>CD38<jats:sup>hi<\/jats:sup> T cells expressed high levels of <jats:italic>CD4<\/jats:italic> mRNA and canonical type 1 regulatory T\u2010cell (TR1) genes including <jats:italic>IL10<\/jats:italic>, <jats:italic>IFNG<\/jats:italic>, <jats:italic>LAG3<\/jats:italic> and <jats:italic>HAVCR2<\/jats:italic> (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co\u2010expression of CD4 and CD38 (CD4<jats:sup>hi<\/jats:sup>CD38<jats:sup>hi<\/jats:sup>) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T\u2010cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1209","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T03:52:25Z","timestamp":1606276345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A population of CD4<sup>hi<\/sup>CD38<sup>hi<\/sup> T cells correlates with disease severity in patients with acute malaria"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-0820","authenticated-orcid":false,"given":"Simon H","family":"Apte","sequence":"first","affiliation":[{"name":"Infectious Diseases Program QIMR Berghofer Medical Research Institute Brisbane QLD Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Minigo","sequence":"additional","affiliation":[{"name":"Global and Tropical 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