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 IFN?-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.

Authors	Montes de Oca, Marcela; de Labastida Rivera, Fabian; Winterford, Clay; Frame, Teija C M; Ng, Susanna S; Amante, Fiona H; Edwards, Chelsea L; Bukali, Luzia; Wang, Yulin; Uzonna, Jude E; Kuns, Rachel D; Zhang, Ping; Kabat, Agnieszka; Klein Geltink, Ramon I; Pearce, Edward J; Hill, Geoffrey R; Engwerda, Christian R
Journal	PLOS PATHOGENS
Pages	e1008994
Volume	16
Date	1/10/2020
Grant ID
Funding Body	Queensland State Government
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1371/journal.ppat.1008994