Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.
This work was supported by a Dale F. Frey Breakthrough Scientist Award from the Damon Runyon Cancer Research Foundation (Grant DFS-09-14 to C.A.L.) and by National Institutes of Health Grant AI-47450 (to G.D.G.).
The microarray data presented in this article have been submitted to the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/gds) under accession number GSE68017.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Crohn disease
- extracellular acidification rate
- gene set enrichment analysis
- hypoxia-inducible factor-1α
- inflammatory bowel disease
- lamina propria mononuclear cell
- oxygen consumption rate
- oxidative phosphorylation
- pyruvate dehydrogenase kinase, isozyme 1
- pentose phosphate pathway
- retinoic acid–related orphan receptor
- small interfering RNA
- tricarboxylic acid
- 2,4,6-trinitrobenzenesulfonic acid
- ulcerative colitis.
- Received May 9, 2016.
- Accepted January 30, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.