Science for Health
31 January 2012
Scientists at NIMR have uncovered the source of a critical molecule that helps to control immune–mediated pathology in malaria. The research is published in The Journal of Immunology, and is featured in the “In This Issue” section, among the top 10% of articles published in the journal.
Infection with the malaria parasite, Plasmodium, causes an inflammatory response in the host. Although important for the clearance of the parasite this response can lead to severe immune-mediated pathology. The host needs to establish a precise balance between the strength of the proinflammatory response triggered by infection and the consecutive immune regulatory mechanisms in order to guarantee efficient clearance of the parasite without excessive tissue damage.
Interleukin (IL)-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during an acute Plasmodium chabaudi infection in mice. IL-10 is produced by different immune cell types, including B cells, macrophages, dendritic cells and several T cell subsets, such as CD8+ and CD4+ T cells, including IFN-g-producing Th1 cells as well as Foxp3+ T regulatory T cells (Tregs). Despite intensive research on the mechanisms responsible for regulation of immunopathology in malaria, the cellular source of protective IL-10 was not known.
Jean Langhorne (pictured), from NIMR’s Division of Parasitology, in collaboration with Anne O’Garra from the Division of Immunoregulation, have demonstrated that T cell-derived IL-10 is necessary for the control of pathology during acute malaria. They found that mice bearing specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il10-/- mice, with significant weight loss, drop in temperature and increased mortality. They also showed that IFN-γ+ Th1 cells are the main producers of the protective IL-10 throughout acute infection and not Foxp3+ Tregs. Finally they demonstrated that the induction of IL-10 in Th1 cells requires direct IL-27 signaling, but is independent of IL-21.
These findings are of the real importance for the malaria field as they define the critical cellular source of protective IL-10 and the pathways leading to its production. This knowledge has significant impact in this field and might be important for the establishment of protocols for manipulation of these pathways in order to prevent severe malaria in humans. The next obvious step will be to validate these observations in human malaria in endemic areas and to define ways to target IL-10-production from particular immune subsets and sites in malaria models in mice.
IL-27 promotes IL-10 production by effector Th1 CD4+ T cells; a critical mechanism for protection from severe immunopathology during malaria infection
Ana Paula Freitas do Rosario, Tracey Lamb, Philip Spence, Robin Stephens, Agathe Lang, Axel Roers, Werner Muller, Anne O’Garra, Jean Langhorne (2012)Journal of Immunology, 188:1178-90. Publisher abstract.
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