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

Henrique Borges da Silva, Raíssa Fonseca, Alexandra dos Anjos Cassado, Érika Machado de Salles, Maria Nogueira de Menezes, Jean Langhorne, Katia Regina Perez, Iolanda Midea Cuccovia, Bernhard Ryffel, Vasco M. Barreto, Cláudio Romero Farias Marinho, Silvia Beatriz Boscardin, José Maria Álvarez, Maria Regina D’Império-Lima, Carlos Eduardo Tadokoro

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Abstract

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.

Original languageEnglish (US)
Article numbere1004598
JournalPLoS pathogens
Volume11
Issue number2
DOIs
StatePublished - Jan 1 2015

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Borges da Silva, H., Fonseca, R., Cassado, A. D. A., Machado de Salles, É., de Menezes, M. N., Langhorne, J., Perez, K. R., Cuccovia, I. M., Ryffel, B., Barreto, V. M., Marinho, C. R. F., Boscardin, S. B., Álvarez, J. M., D’Império-Lima, M. R., & Tadokoro, C. E. (2015). 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. PLoS pathogens, 11(2), [e1004598]. https://doi.org/10.1371/journal.ppat.1004598