TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression

Eur J Immunol. 2015 Apr;45(4):1010-8. doi: 10.1002/eji.201444726. Epub 2015 Feb 11.

Abstract

Differentiated CD4(+) T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ(+) IL-17(+) CD4(+) T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ(+) Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γ(Thy1.1+) Th1 cells were generated by culturing naïve CD4(+) T cells from IFN-γ(Thy1.1) CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-γ(Thy1.1+) Th1 cells induced colitis in Rag(-/-) mice after adoptive transfer and converted into IL-17(+) Th17, but not Foxp3(+) Treg cells in the inflamed intestines. TGF-β and IL-6, but not IL-1β and IL-23, regulated Th1 conversion into Th17 cells. TGF-β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and ROR-γt-binding sites on il-17 or rorc gene in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-β induction of Runx1.

Keywords: Colitis; Runx1; TGF-β; Th1; Th17.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Colitis / immunology
  • Core Binding Factor Alpha 2 Subunit / biosynthesis*
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Flagellin / immunology
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Interferon-gamma / biosynthesis
  • Interleukin-17 / biosynthesis
  • Interleukin-1beta / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-23 / metabolism
  • Interleukin-6 / metabolism
  • Intestinal Mucosa / immunology*
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / biosynthesis
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / biosynthesis
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Th1 Cells / cytology*
  • Th1 Cells / immunology
  • Th17 Cells / cytology*
  • Th17 Cells / immunology
  • Transforming Growth Factor beta / metabolism*

Substances

  • CBir1 flagellin
  • Core Binding Factor Alpha 2 Subunit
  • Histones
  • Homeodomain Proteins
  • IL1B protein, mouse
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-2
  • Interleukin-23
  • Interleukin-6
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RNA, Small Interfering
  • Rora protein, mouse
  • Rorc protein, mouse
  • Runx1 protein, mouse
  • Transforming Growth Factor beta
  • Flagellin
  • RAG-1 protein
  • Interferon-gamma