Mission: Immuno-Possible!

Malaria remains one of the world’s deadliest infectious diseases, caused by Plasmodium parasites and transmitted by mosquitoes. To control and clear the infection, the immune system relies on a coordinated response involving various cell types, including T cells, B cells, and specialized antigen-presenting cells (APCs). Dendritic cells (DCs) are among the best-known APCs, but even in their absence, some T cell activity persists, raising the question: who else is helping? The Molecular Parasitology Group (Kai Matuschewski) explored this question in detail using a mouse model of Plasmodium yoelii infection. Their new findings reveal that macrophages in the spleen, especially those in the marginal zone and red pulp, play a crucial supporting role. These cells not only help activate CD4+ T cells but also directly contribute to clearing infected red blood cells. By selectively depleting different macrophage subsets, The Molecular Parasitology Group uncovered distinct and essential roles for each type. These insights highlight the complex interplay between immune cells during malaria and open up new avenues for understanding how the body defends itself against this persistent pathogen. Find out more in their Frontiers in Immunology Article!

Abstract

Malaria, caused by the parasite Plasmodium 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 IFNγ response. In a previous study, we demonstrated that dendritic cell (DC) depletion resulted in impaired T cell responses. However, substantial CD4 + and CD8 + 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 (MZMΦ), and marginal metallophilic macrophages (MMMΦ) with an altered cytokine profile in DC-deficient mice upon P. yoelii 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 P. yoelli infections in two transgenic C57BL/6 mouse lines. Treatment of CD169DTR mice with diphtheriatoxin (DT) efficiently depleted MMMΦ and MZMΦ, resulting in reduced IFNγ production by CD4 + T cells in P. yoelii-infected mice, though parasitemia progression was not modulated. In marked contrast, specific red pulp macrophages (RPMΦ) depletion in SpiC flox/flox 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 + T cell activation, and that RPMΦs are indispensable for clearing of infected red blood cells (iRBCs) during P. yoelii infection.