{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T22:53:16Z","timestamp":1788562396423,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI103666, AI128735"],"award-info":[{"award-number":["AI103666, AI128735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["K12GM102779, T32A170117, R25GM104547"],"award-info":[{"award-number":["K12GM102779, T32A170117, R25GM104547"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    T cells expressing high levels of inhibitory receptors such as PD-1 and LAG-3 are a hallmark of chronic infections and cancer. Checkpoint blockade therapies targeting these receptors have been largely validated as promising strategies to restore exhausted T cell functions and clearance of chronic infections and tumors. The inability to develop long-term natural immunity in malaria-infected patients has been proposed to be at least partially accounted for by sustained expression of high levels of inhibitory receptors on T and B lymphocytes. While blockade or lack of PD-1\/PD-L1 and\/or LAG-3 was reported to promote better clearance of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    parasites in various mouse models, how exactly blockade of these pathways contributes to enhanced protection is not known. Herein, using the mouse model of non-lethal\n                    <jats:italic>P. yoelii (Py)<\/jats:italic>\n                    infection, we reveal that the kinetics of blood parasitemia as well as CD4\n                    <jats:sup>+<\/jats:sup>\n                    T follicular helper (T\n                    <jats:sub>FH<\/jats:sub>\n                    ) and germinal center (GC) B cell responses are indistinguishable between PD-1\n                    <jats:sup>-\/-<\/jats:sup>\n                    , PD-L1\n                    <jats:sup>-\/-<\/jats:sup>\n                    and WT mice. Yet, we also report that monoclonal antibody (mAb) blockade of LAG-3 in PD-L1\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice promotes accelerated control of blood parasite growth and clearance, consistent with prior therapeutic blockade experiments. However, neither CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>FH<\/jats:sub>\n                    and GC B cell responses, nor parasite-specific Ab serum titers and capacity to transfer protection differed. We also found that i) the majority of LAG-3\n                    <jats:sup>+<\/jats:sup>\n                    cells are T cells, ii) selective depletion of CD4\n                    <jats:sup>+<\/jats:sup>\n                    but not CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells prevents anti-LAG-3-mediated protection, and iii) production of effector cytokines by CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells is increased in anti-LAG-3-treated versus control mice. Thus, taken together, these results are consistent with a model in which blockade and\/or deficiency of PD-L1 and LAG-3 on parasite-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells unleashes their ability to effectively clear blood parasites, independently from humoral responses.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2020.576743","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T09:01:59Z","timestamp":1610614919000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Blockade of LAG-3 in PD-L1-Deficient Mice Enhances Clearance of Blood Stage Malaria Independent of Humoral Responses"],"prefix":"10.3389","volume":"11","author":[{"given":"Raquel","family":"Furtado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Chorro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Zimmerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Guillen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Spaulding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu Shien","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna 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