{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:34:51Z","timestamp":1791272091228,"version":"4.1.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Naturally acquired immunity to malaria develops slowly, requiring several years of repeated exposure to be effective. The cellular and molecular factors underlying this observation are only partially understood. Recent studies suggest that chronic Plasmodium falciparum exposure may induce functional exhaustion of lymphocytes, potentially impeding optimal control of infection. However, it remains unclear whether the \u201catypical\u201d memory B cells (MBCs) and \u201cexhausted\u201d CD4 T cells described in humans exposed to endemic malaria are driven by P. falciparum per se or by other factors commonly associated with malaria, such as coinfections and malnutrition. To address this critical question we took advantage of a \u201cnatural\u201d experiment near Kilifi, Kenya, and compared profiles of B and T cells of children living in a rural community where P. falciparum transmission is ongoing to the profiles of age-matched children living under similar conditions in a nearby community where P. falciparum transmission ceased 5 y prior to this study. We found that continuous exposure to P. falciparum drives the expansion of atypical MBCs. Persistent P. falciparum exposure was associated with an increased frequency of CD4 T cells expressing phenotypic markers of exhaustion, both programmed cell death-1 (PD-1) alone and PD-1 in combination with lymphocyte-activation gene-3 (LAG-3). This expansion of PD-1\u2013expressing and PD-1\/LAG-3\u2013coexpressing CD4 T cells was largely confined to CD45RA+ CD4 T cells. The percentage of CD45RA+CD27+ CD4 T cells coexpressing PD-1 and LAG-3 was inversely correlated with frequencies of activated and classical MBCs. Taken together, these results suggest that P. falciparum infection per se drives the expansion of atypical MBCs and phenotypically exhausted CD4 T cells, which has been reported in other endemic areas.<\/jats:p>","DOI":"10.4049\/jimmunol.1202438","type":"journal-article","created":{"date-parts":[[2012,12,22]],"date-time":"2012-12-22T02:13:02Z","timestamp":1356142382000},"page":"1038-1047","source":"Crossref","is-referenced-by-count":274,"title":["Chronic Exposure to\n                    <i>Plasmodium falciparum<\/i>\n                    Is Associated with Phenotypic Evidence of B and T Cell Exhaustion"],"prefix":"10.1093","volume":"190","author":[{"given":"Joseph","family":"Illingworth","sequence":"first","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]},{"name":"Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford OX3 7LJ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah S","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center , Oklahoma City, OK 73104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Roetynck","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]},{"name":"Division of Parasitology, National Institute for Medical Research , London NW7 1AA,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jedida","family":"Mwacharo","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan K","family":"Pierce","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20852"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Bejon","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]},{"name":"Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford OX3 7LJ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D","family":"Crompton","sequence":"additional","affiliation":[{"name":"Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20852"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Marsh","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]},{"name":"Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford OX3 7LJ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis M","family":"Ndungu","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute, Centre for Geographical Medicine Research (Coast) , Kilifi,","place":["Kenya"]},{"name":"Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford , Oxford OX3 7LJ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,2,1]]},"reference":[{"key":"2025032406303523200_r1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/192733a0","article-title":"Gamma-globulin and acquired immunity to human malaria","volume":"192","author":"Cohen","year":"1961","journal-title":"Nature"},{"key":"2025032406303523200_r2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.4269\/ajtmh.1991.45.297","article-title":"Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria","volume":"45","author":"Sabchareon","year":"1991","journal-title":"Am. 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