Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells

Eléonore Beurel, Wen I. Yeh, Suzanne M. Michalek, Laurie E. Harrington, Richard S. Jope

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

CD4+ T cells are critical for host defense but are also major drivers of immune-mediated diseases. The classical view of Th1 and Th2 subtypes of CD4+ T cells was recently revised by the identification of the Th17 lineage of CD4+ T cells that produce IL-17, which have been found to be critical in the pathogenesis of autoimmune and other diseases. Mechanisms controlling the differentiation of Th17 cells have been well described, but few feasible targets for therapeutically reducing Th17 cells are known. The generation of Th17 cells requires IL-6 and activation of STAT3. During polarization of CD4+ T cells to Th17 cells, we found that inhibition of glycogen synthase kinase-3 (GSK3) blocked IL-6 production, STAT3 activation, and polarization to Th17 cells. Polarization of CD4+ T cells to Th17 cells increased by 10-fold the expression of GSK3β protein levels in Th17 cells, whereas GSK3β was unaltered in regulatory T cells. Diminishing GSK3 activity either pharmacologically or molecularly blocked Th17 cell production, and increasing GSK3 activity promoted polarization to Th17 cells. In vivo inhibition of GSK3 in mice depleted constitutive Th17 cells in intestinal mucosa, blocked Th17 cell generation in the lung after Francisella tularensis infection, and inhibited the increase in spinal cord Th17 cells and disease symptoms in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. These findings identify GSK3 as a critical mediator of Th17 cell production and indicate that GSK3 inhibitors provide a potential therapeutic intervention to control Th17-mediated diseases.

Original languageEnglish (US)
Pages (from-to)1391-1398
Number of pages8
JournalJournal of Immunology
Volume186
Issue number3
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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