IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection

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 + CD4 + T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4 + 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.

IL-30† (IL-27A): a familiar stranger in immunity, inflammation, and cancer

“…Similar IL-27-dependent regulation of CD4 T cell immunity was also noted in an African trypanosome infection model 69 . Montes de Oca et al recently reported a similar finding in a Leishmania infection model, in which IL-27R deficiency significantly expedited parasite clearance at the expense of enhanced tissue damage caused by an imbalance in antigen-specific Th1- and Tr1-type CD4 T cells 70 . Interestingly, IL-27 exerted these effects by regulating the metabolic profiles of Th1-type CD4 T cells 70 .…”

“…Montes de Oca et al recently reported a similar finding in a Leishmania infection model, in which IL-27R deficiency significantly expedited parasite clearance at the expense of enhanced tissue damage caused by an imbalance in antigen-specific Th1- and Tr1-type CD4 T cells 70 . Interestingly, IL-27 exerted these effects by regulating the metabolic profiles of Th1-type CD4 T cells 70 . IL-27Rα −/− CD4 T cells were more glycolytic, suggesting that IL-27 seems to limit Th1 cell glycolysis to further protect against tissue pathology during infection.…”

The Chemokine Receptor CCR5 Links Memory CD4+ T Cell Metabolism to T Cell Antigen Receptor Nanoclustering

“…OT-II WT and CCR5 -/- lymphoblasts were incubated for 24 h with 2-DG, and the inhibitor then removed before co-incubation with irradiated splenocytes pre-loaded with different doses of the OVA 323-339 peptide. Since glycolysis activation is required for complete T cell activation ( 14 – 17 ), IL-2 production and T cell proliferation were analyzed shortly after re-stimulation. IL-2 production was seen to increase significantly in the 2-DG-treated CCR5 -/- lymphoblasts compared to controls in an antigen dose-dependent manner ( Figure 5C ).…”

“…The inhibition of glycolysis seems to be important for the generation of long-lived CD8 + T M cells (19,20), but it also has a negative impact on CD4 + and CD8 + T cell activation (14)(15)(16)(17). This renders it counterintuitive to associate the increased TCR nanoclustering induced by 2-DG treatment in CCR5 -/lymphoblasts with increased sensitivity upon antigen recall.…”

“…The net result is a metabolic switchover that reduces the OXPHOS/glycolytic ratio in these cells. This increase in glycolysis, which occurs in CD8 + and all effector CD4 + T helper (Th) subsets (Th1, Th2 and Th17), is not only important for generating the biomass needed for the expansion of activated cells, it is also required for the expression of cytokines involved in T cell effector function (14)(15)(16)(17). In contrast, the metabolism of CD4 + regulatory T cells, and of both CD4 + and CD8 + T M cells, largely relies on OXPHOS and fatty acid oxidation (FAO) (12,16,18).…”