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

• Main Authors: Marcela Montes de Oca, Fabian de Labastida Rivera, Clay Winterford, Teija C M Frame, Susanna S Ng, Fiona H Amante, Chelsea L Edwards, Luzia Bukali, Yulin Wang, Jude E Uzonna, Rachel D Kuns, Ping Zhang, Agnieszka Kabat, Ramon I Klein Geltink, Edward J Pearce, Geoffrey R Hill, Christian R Engwerda
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2020-10-01
• Series: PLoS Pathogens
• Online Access: https://doi.org/10.1371/journal.ppat.1008994

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.