IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection
Marcela Montes de, Fabian de Labastida Rivera, Clay Winterford, Teija Frame, Susanna S. Ng, Fiona H. Amante, Chelsea L. Edwards, Luzia Bukali, Yulin Wang, Jude E. Uzonna, Rachel D. Kuns, Ping Zhang, Agnieszka M. Kabat, Ramon I. Klein Geltink, Edward J. Pearce, Geoffrey R. Hill, Christian Engwerda
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.