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Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti- Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria. 

Cells of all kinds often wage chemical warfare against each other. Hydrogen peroxide is often the weapon of choice on the microscopic battlefield, where it is used to incapacitate opponents or to defend against attackers. For example, some plants produce hydrogen peroxide in response to infection to fight off disease-causing microbes. Individual cells have also evolved defenses to prevent or repair ‘injuries’ caused by hydrogen peroxide. These are similar across many different species. They include enzymes called catalases, which break down hydrogen peroxide, and others to repair damage. However, scientists still do not fully understand how animals and other multicellular organisms might coordinate these defenses across their cells. Caenorhabditis elegans is a microscopic species of worm that lives in rotting fruits. It often encounters the threat of cellular warfare: many types of bacteria in its environment generate hydrogen peroxide, and some can make enough to kill the worms outright. Like other organisms, C. elegans also produces catalases to defend itself against hydrogen peroxide attacks. However, it must activate its defenses at the right time; if it did so when they were not needed, this would result in a detrimental energy ‘cost’ to the worm. Although C. elegans is a small organism containing only a defined number of cells, exactly why and how it switches its chemical defenses on or off remains unknown. Schiffer et al. therefore set out to determine how C. elegans controls these defenses, focusing on the role of the brain in detecting and processing information from its environment. Experiments looking at the brains of genetically manipulated worms revealed a circuit of sensory nerve cells whose job is to tell the rest of the worm’s tissues that they no longer need to produce defense enzymes. Crucially, the circuit became active when the worms sensed E. coli bacteria nearby. Bacteria in the same family as E. coli are normally found in in the same habitat as C. elegans and these bacteria are also known to make enzymes of their own to eliminate hydrogen peroxide around them. These results indicate that C. elegans can effectively decide, based on the activity of its circuit, when to use its own defenses and when to ‘freeload’ off those of neighboring bacteria. This work is an important step towards understanding how sensory circuits in the brain can control hydrogen peroxide defenses in multicellular organisms. In the future, it could help researchers work out how more complex animals, like humans, coordinate their cellular defenses, and therefore potentially yield new strategies for improving health and longevity.