PMID- 25658925 OWN - NLM STAT- MEDLINE DCOM- 20160114 LR - 20190202 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 11 IP - 2 DP - 2015 Feb TI - In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria. PG - e1004598 LID - 10.1371/journal.ppat.1004598 [doi] LID - e1004598 AB - Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection. FAU - Borges da Silva, Henrique AU - Borges da Silva H AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil; Instituto Gulbenkian de Ciencia, Oeiras, Portugal. FAU - Fonseca, Raissa AU - Fonseca R AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Cassado, Alexandra Dos Anjos AU - Cassado Ados A AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Machado de Salles, Erika AU - Machado de Salles E AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - de Menezes, Maria Nogueira AU - de Menezes MN AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Langhorne, Jean AU - Langhorne J AD - Medical Research Center, London, United Kingdom. FAU - Perez, Katia Regina AU - Perez KR AD - Departamento de Biofisica, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brasil. FAU - Cuccovia, Iolanda Midea AU - Cuccovia IM AD - Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Ryffel, Bernhard AU - Ryffel B AD - Unite d'Immunologie et Neurogenetique Experimentales et Moleculaires (CNRS-UMR7355), Universite d'Orleans, Orleans, France. FAU - Barreto, Vasco M AU - Barreto VM AD - Instituto Gulbenkian de Ciencia, Oeiras, Portugal. FAU - Marinho, Claudio Romero Farias AU - Marinho CR AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Boscardin, Silvia Beatriz AU - Boscardin SB AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Alvarez, Jose Maria AU - Alvarez JM AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - D'Imperio-Lima, Maria Regina AU - D'Imperio-Lima MR AD - Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil. FAU - Tadokoro, Carlos Eduardo AU - Tadokoro CE AD - Instituto Gulbenkian de Ciencia, Oeiras, Portugal. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150206 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 SB - IM MH - Animals MH - CD4-Positive T-Lymphocytes/*immunology MH - Dendritic Cells/*immunology MH - Disease Models, Animal MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Lymphocyte Activation/*immunology MH - Malaria/*immunology MH - Mice MH - Mice, Inbred C57BL MH - Microscopy, Confocal MH - Parasitemia/immunology MH - Phagocytosis/immunology MH - Plasmodium chabaudi MH - Spleen/immunology/parasitology PMC - PMC4450059 COIS- The authors have declared that no competing interests exist. EDAT- 2015/02/07 06:00 MHDA- 2016/01/15 06:00 PMCR- 2015/02/06 CRDT- 2015/02/07 06:00 PHST- 2013/12/18 00:00 [received] PHST- 2014/12/02 00:00 [accepted] PHST- 2015/02/07 06:00 [entrez] PHST- 2015/02/07 06:00 [pubmed] PHST- 2016/01/15 06:00 [medline] PHST- 2015/02/06 00:00 [pmc-release] AID - PPATHOGENS-D-13-03331 [pii] AID - 10.1371/journal.ppat.1004598 [doi] PST - epublish SO - PLoS Pathog. 2015 Feb 6;11(2):e1004598. doi: 10.1371/journal.ppat.1004598. eCollection 2015 Feb.