Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved August 1, 2018 (received for review April 3, 2018)
Th17 cells favor glycolytic metabolism. Pyruvate dehydrogenase, which facilitates entry into the oxidative phosphorylation circle, is inhibited by pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2). Our studies demonstrate that the transcription factor ICER/CREM, which is known to promote Th17 differentiation and related pathology, suppresses the expression of PDP2 and diverts energy production into the glycolytic pathway. In lupus-prone mice and people with systemic lupus erythematosus, PDP2 levels are decreased and its replenishment suppresses Th17 differentiation.
Th17 cells favor glycolytic metabolism, and pyruvate dehydrogenase (PDH) is the key bifurcation enzyme, which in its active dephosphorylated form advances the oxidative phosphorylation from glycolytic pathway. The transcriptional factor, inducible cAMP early repressor/cAMP response element modulator (ICER/CREM), has been shown to be induced in Th17 cells and to be overexpressed in CD4+ T cells from the patients with systemic lupus erythematosus (SLE). We found that glycolysis and lactate production in in vitro Th17-polarized T cells was reduced and that the expression of pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2), an enzyme that converts the inactive PDH to its active form, and PDH enzyme activity were increased in Th17 cells from ICER/CREM-deficient animals. ICER was found to bind to the Pdp2 promoter and suppress its expression. Furthermore, forced expression of PDP2 in CD4+ cells reduced the in vitro Th17 differentiation, whereas shRNA-based suppression of PDP2 expression increased in vitro Th17 differentiation and augmented experimental autoimmune encephalomyelitis. At the translational level, PDP2 expression was decreased in memory Th17 cells from patients with SLE and forced expression of PDP2 in CD4+ T cells from lupus-prone MRL/lpr mice and patients with SLE suppressed Th17 differentiation. These data demonstrate the direct control of energy production during Th17 differentiation in health and disease by the transcription factor ICER/CREM at the PDH metabolism bifurcation level.
↵1M.K. and N.Y. contributed equally to this work.
Author contributions: M.K., N.Y., and G.C.T. designed research; M.K., N.Y., K.M., N.E.S., W.P., V.C.K., and M.G.T. performed research; M.K. and N.Y. contributed new reagents/analytic tools; M.K., N.Y., and K.M. analyzed data; and M.K., N.Y., and G.C.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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