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IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection.
- Source :
- PLoS Pathogens; 10/13/2020, Vol. 16 Issue 10, p1-24, 24p
- Publication Year :
- 2020
-
Abstract
- Inflammation is critical for controlling pathogens, but also responsible for symptoms of infectious diseases. IL-27 is an important regulator of inflammation and can limit development of IFNγ-producing Tbet<superscript>+</superscript> CD4<superscript>+</superscript> T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4<superscript>+</superscript> T cells, but the underlying mechanisms of these immunoregulatory pathways are not clear. Here we studied the role of IL-27 signalling in experimental visceral leishmaniasis (VL) caused by infection of C57BL/6 mice with the human pathogen Leishmania donovani. We found IL-27 signalling was critical for the development of IL-10-producing Th1 (Tr1) cells during infection. Furthermore, in the absence of IL-27 signalling, there was improved control of parasite growth, but accelerated splenic pathology characterised by the loss of marginal zone macrophages. Critically, we discovered that IL-27 signalling limited glycolysis in Th1 cells during infection that in turn attenuated inflammation. Furthermore, the modulation of glycolysis in the absence of IL-27 signalling restricted tissue pathology without compromising anti-parasitic immunity. Together, these findings identify a novel mechanism by which IL-27 mediates immune regulation during disease by regulating cellular metabolism. Author summary: Infectious diseases like visceral leishmaniasis caused by the protozoan parasites Leishmania donovani and L. infantum are associated with an inflammatory response generated by the host. This is needed to control parasite growth, but also contributes to the symptoms of disease. Consequently, these inflammatory responses need to be tightly regulated. Although we now recognize many of the cells and molecules involved in controlling inflammation, the underlying mechanisms mediating immune regulation are unclear. CD4<superscript>+</superscript> T cells are critical drivers of inflammatory responses during infections and as they progress from a naïve to activated state, the metabolic pathways they use have to change to meet the new energy demands required to proliferate and produce effector molecules. In this study, we discovered that the inflammatory CD4<superscript>+</superscript> T cells needed to control L. donovani infection switch from relying on mitochondrial oxidative pathways to glycolysis. Critically, we found the cytokine IL-27 limited glycolysis in these inflammatory CD4<superscript>+</superscript> T cells, and in the absence of IL-27 signaling pathways, these cells expanded more rapidly to better control parasite growth, but also caused increased tissue damage in the spleen. However, pharmacological dampening of glycolysis in inflammatory CD4<superscript>+</superscript> T cells in L. donovani-infected mice lacking IL-27 signaling pathways limited tissue damage without affecting their improved anti-parasitic activity. Together, these results demonstrate that the pathogenic activity of inflammatory CD4<superscript>+</superscript> T cells can be modulated by altering their cellular metabolism. [ABSTRACT FROM AUTHOR]
- Subjects :
- TH1 cells
GLYCOLYSIS
INFLAMMATION
VISCERAL leishmaniasis
T cells
SYMPTOMS
Subjects
Details
- Language :
- English
- ISSN :
- 15537366
- Volume :
- 16
- Issue :
- 10
- Database :
- Complementary Index
- Journal :
- PLoS Pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 146408912
- Full Text :
- https://doi.org/10.1371/journal.ppat.1008994