{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:03:34Z","timestamp":1787022214494,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013565","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005492","name":"Stanford University","doi-asserted-by":"publisher","award":["Innovative Medicines Accelerator: Vaccine Prototyping using Tonsils-in-a-Dish"],"award-info":[{"award-number":["Innovative Medicines Accelerator: Vaccine Prototyping using Tonsils-in-a-Dish"]}],"id":[{"id":"10.13039\/100005492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"A.P. Giannini Fellowship"},{"name":"Walter V. And Idun Berry Fellowship"},{"DOI":"10.13039\/501100020480","name":"CSL Limited","doi-asserted-by":"publisher","award":["Centenary Fellowship"],"award-info":[{"award-number":["Centenary Fellowship"]}],"id":[{"id":"10.13039\/501100020480","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023410","name":"Snow Medical","doi-asserted-by":"publisher","award":["2022\/SF167"],"award-info":[{"award-number":["2022\/SF167"]}],"id":[{"id":"10.13039\/501100023410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015521","name":"Stanford Maternal and Child Health Research Institute","doi-asserted-by":"publisher","award":["Woods Family Faculty Scholar in Pediatric Translational Medicine"],"award-info":[{"award-number":["Woods Family Faculty Scholar in Pediatric Translational Medicine"]}],"id":[{"id":"10.13039\/100015521","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["R01 AI189963"],"award-info":[{"award-number":["R01 AI189963"]}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["Independent Research Institutes Infrastructure Support Scheme"],"award-info":[{"award-number":["Independent Research Institutes Infrastructure Support Scheme"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["Victorian State Government Operational Infrastructure Support"],"award-info":[{"award-number":["Victorian State Government Operational Infrastructure Support"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Vaccine effectiveness against malaria is dramatically reduced in malaria-exposed compared to malaria-na\u00efve populations, potentially due to altered immune responses in secondary lymphoid organs following repeated infection. Newly developed human tonsil and spleen organoids, which replicate key features of B and T cell immunity, provide an exciting opportunity to overcome challenges of other models and to improve our understanding of innate-adaptive interactions in lymphoid tissue. The objectives of this study were to use these organoids to investigate the impact of malaria parasites on 1) cells within lymphoid tissues and 2) responses to a heterologous antigen. When we exposed organoids from malaria-na\u00efve donors to\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    -infected red blood cells (iRBC), we observed that iRBC exposure did not disrupt organoid formation and significantly increased V\u03b42\u2009+\u2009\u03b3\u03b4 T cell frequencies in both tonsil and spleen organoids at multiple timepoints. Single-cell RNA\/TCR sequencing revealed that iRBC-responsive V\u03b42\u2009+\u2009T cells in organoids were clonally expanded and exhibited activated, cytotoxic phenotypes with upregulated expression of granzymes, interferon-stimulated genes, and antigen presentation machinery. TCR repertoire analysis demonstrated that malaria exposure drove clonal expansion of cytotoxic V\u03b42\u2009+\u2009T cells, contrasting with the diverse, smaller clones observed in control conditions. To validate these findings, we analyzed tonsils from Ugandan children with asymptomatic parasitemia and found expanded V\u03b42\u2009+\u2009T cells with enhanced cytotoxic potential compared to uninfected controls. When we tested whether malaria pre-exposure affected subsequent recall responses to influenza vaccine, malaria pre-exposure or \u03b3\u03b4 T cell depletion did not significantly alter cellular frequencies or influenza-specific antibody responses in most donors, though modest reductions were observed in some individuals. This work demonstrates the utility of human lymphoid organoids for studying malaria-host interactions and provides novel insights into V\u03b42\u2009+\u2009T cell biology, including evidence for clonal expansion and cytotoxic differentiation in response to malaria parasites within secondary lymphoid tissues.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013565","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:48:51Z","timestamp":1775843331000},"page":"e1013565","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cytotoxic V\u03b42+ T cell subsets expand in response to malaria in human tonsil and spleen organoids"],"prefix":"10.1371","volume":"22","author":[{"given":"Kathleen D.","family":"Press","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Bach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Sola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie","family":"Camanag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas 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