{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:18:36Z","timestamp":1792459116575,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Malaria, caused by the parasite <jats:italic>Plasmodium<\/jats:italic> spp., remains the most prevalent and dangerous vector-borne infectious disease worldwide. Effective pathogen clearance during malaria hinges on the interplay between adaptive and innate immune responses, especially on T cells, B cells, antigen-presenting cells (APCs) and IFN\u03b3 response. In a previous study, we demonstrated that dendritic cell (DC) depletion resulted in impaired T cell responses. However, substantial CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cell activation was still detectable, suggesting that other APCs compensate for the lack of DCs. In the present study, we report an increase in splenic marginal zone macrophages (MZM\u03a6), and marginal metallophilic macrophages (MMM\u03a6) with an altered cytokine profile in DC-deficient mice upon <jats:italic>P. yoelii<\/jats:italic> infection. Ablation of macrophages by clodronate liposome (CL) application resulted in partially reduced T cell activation, which correlated with elevated parasitemia. To further elucidate the specific role of splenic macrophage subsets we studied <jats:italic>P. yoelli<\/jats:italic> infections in two transgenic C57BL\/6 mouse lines. Treatment of CD169DTR mice with diphtheriatoxin (DT) efficiently depleted MMM\u03a6 and MZM\u03a6, resulting in reduced IFN\u03b3 production by CD4<jats:sup>+<\/jats:sup> T cells in <jats:italic>P. yoelii<\/jats:italic>-infected mice, though parasitemia progression was not modulated. In marked contrast, specific red pulp macrophages (RPM\u03a6) depletion in SpiC<jats:sup>flox\/flox<\/jats:sup> x vav1cre mice resulted in elevated parasitemia. In conclusion, our data provide evidence that splenic macrophages located in or at the marginal zone contribute to CD4<jats:sup>+<\/jats:sup> T cell activation, and that RPM\u03a6s are indispensable for clearing of infected red blood cells (iRBCs) during <jats:italic>P. yoelii<\/jats:italic> infection.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1607201","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:54Z","timestamp":1752729894000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Red pulp macrophages clear parasites, while marginal metallophilic and marginal zone macrophages support CD4+ T cell activation during Plasmodium yoelii infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Julia","family":"Falkenstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ninnemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrahman","family":"Elwy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl S.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Matuschewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Buer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Westendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"B1","volume-title":"World Malaria Report 2024","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.f.205","article-title":"Immunity to malaria: more questions than answers","volume":"9","author":"Langhorne","year":"2008","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00463","article-title":"Malaria Parasites: The great escape","volume":"7","author":"Renia","year":"2016","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nri1311","article-title":"Innate immunity to malaria","volume":"4","author":"Stevenson","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-00486-7","article-title":"Bystander CD4(+) T cells: crossroads between innate and adaptive immunity","volume":"52","author":"Lee","year":"2020","journal-title":"Exp Mol Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.0105-2896.2004.00182.x","article-title":"Dendritic cells, pro-inflammatory responses, and antigen presentation in a rodent malaria infection","volume":"201","author":"Langhorne","year":"2004","journal-title":"Immunol Rev"},{"key":"B7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1111\/imr.12804","article-title":"The regulation of CD4(+) T cells during malaria","volume":"293","author":"Kumar","year":"2020","journal-title":"Immunol Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev.immunol.19.1.23","article-title":"In vivo activation of antigen-specific CD4 T cells","volume":"19","author":"Jenkins","year":"2001","journal-title":"Annu Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011174","article-title":"The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection","volume":"195","author":"Xu","year":"2002","journal-title":"J Exp Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00671","article-title":"CD4 T-cell subsets in malaria: TH1\/TH2 revisited","volume":"5","author":"Perez-Mazliah","year":"2014","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1146\/annurev.immunol.23.021704.115638","article-title":"Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research","volume":"23","author":"Good","year":"2005","journal-title":"Annu Rev Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI169299","article-title":"IL-10-producing Th1 cells possess a distinct molecular signature in malaria","volume":"133","author":"Edwards","year":"2023","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure and function of the immune system in the spleen","volume":"4","author":"Lewis","year":"2019","journal-title":"Sci Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4RI1020-713R","article-title":"The spleen: \u201cepicenter\u201d in malaria infection and immunity","volume":"110","author":"Ghosh","year":"2021","journal-title":"J Leukoc Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01333","article-title":"Conventional CD11c(high) dendritic cells are important for T cell priming during the initial phase of plasmodium yoelii infection, but are dispensable at later time points","volume":"8","author":"Ueffing","year":"2017","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.pt.2012.10.002","article-title":"Monocytes and macrophages in malaria: protection or pathology","volume":"29","author":"Chua","year":"2013","journal-title":"Trends Parasitol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2011.01741.x","article-title":"The role of the spleen in malaria","volume":"14","author":"Del Portillo","year":"2012","journal-title":"Cell Microbiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12451","article-title":"Tissue-resident macrophages: then and now","volume":"144","author":"Davies","year":"2015","journal-title":"Immunology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxq047","article-title":"Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses","volume":"22","author":"Pereira","year":"2010","journal-title":"Int Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161375","article-title":"Phagocytosis imprints heterogeneity in tissue-resident macrophages","volume":"214","author":"Gonzalez","year":"2017","journal-title":"J Exp Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2018.05.005","article-title":"Origin and specialization of splenic macrophages","volume":"330","author":"Gonzalez","year":"2018","journal-title":"Cell Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01005-07","article-title":"Macrophage-mediated but gamma interferon-independent innate immune responses control the primary wave of Plasmodium yoelii parasitemia","volume":"75","author":"Couper","year":"2007","journal-title":"Infect Immun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01005-15","article-title":"Depletion of phagocytic cells during nonlethal plasmodium yoelii infection causes severe malaria characterized by acute renal failure in mice","volume":"84","author":"Terkawi","year":"2016","journal-title":"Infect Immun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.350","article-title":"CD169(+) macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection","volume":"7","author":"Shaabani","year":"2016","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1046\/j.1440-1711.1998.00709.x","article-title":"Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements","volume":"76","author":"Barnden","year":"1998","journal-title":"Immunol Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1186\/s12936-018-2313-6","article-title":"Application of the automated haematology analyzer XN-30 in an experimental rodent model of malaria","volume":"17","author":"Tougan","year":"2018","journal-title":"Malar J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2622","article-title":"The nuclear receptor LXRalpha controls the functional specialization of splenic macrophages","volume":"14","author":"Gonzalez","year":"2013","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030684","article-title":"Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone","volume":"198","author":"Karlsson","year":"2003","journal-title":"J Exp Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0158-z","article-title":"T cell-mediated immunity to malaria","volume":"19","author":"Kurup","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022003","article-title":"Inhibition of T cell function during malaria: implications for immunology and vaccinology","volume":"197","author":"Urban","year":"2003","journal-title":"J Exp Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103706","article-title":"Phagocytic uptake of oxidized heme polymer is highly cytotoxic to macrophages","volume":"9","author":"Deshmukh","year":"2014","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00700.x","article-title":"Regulation of interleukin-12\/interleukin-23 production and the T-helper 17 response in humans","volume":"226","author":"Lyakh","year":"2008","journal-title":"Immunol Rev"},{"key":"B33","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/0022-1759(94)90012-4","article-title":"Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications","volume":"174","author":"Van Rooijen","year":"1994","journal-title":"J Immunol Methods"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aaw0336","article-title":"Neutrophil extracellular traps drive inflammatory pathogenesis in malaria","volume":"4","author":"Knackstedt","year":"2019","journal-title":"Sci Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.10.006","article-title":"Targeted delivery of antigen to activated CD169(+) macrophages induces bias for expansion of CD8(+) T cells","volume":"26","author":"Edgar","year":"2019","journal-title":"Cell Chem Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1093\/jb\/mvy050","article-title":"CD169 macrophages regulate immune responses toward particulate materials in the circulating fluid","volume":"164","author":"Asano","year":"2018","journal-title":"J Biochem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.010","article-title":"Tissue-resident CD169(+) macrophages form a crucial front line against plasmodium infection","volume":"16","author":"Gupta","year":"2016","journal-title":"Cell Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.01.021","article-title":"Functional CD169 on macrophages mediates interaction with dendritic cells for CD8(+) T cell cross-priming","volume":"22","author":"van Dinther","year":"2018","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.922377","article-title":"Neutrophils in malaria: A double-edged sword role","volume":"13","author":"Babatunde","year":"2022","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nri1669","article-title":"Structure and function of the spleen","volume":"5","author":"Mebius","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.immuni.2013.04.004","article-title":"Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes","volume":"38","author":"Hashimoto","year":"2013","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature07472","article-title":"Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis","volume":"457","author":"Kohyama","year":"2009","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.059","article-title":"Organ-specific fate, recruitment, and refilling dynamics of tissue-resident macrophages during blood-stage malaria","volume":"25","author":"Lai","year":"2018","journal-title":"Cell Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1607201\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:56Z","timestamp":1752729896000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1607201\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2025.1607201"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1607201","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]},"article-number":"1607201"}}