Kruppel-like factor KLF10 targets transforming growth factor-β1 to regulate CD4+ CD25- T cells and T regulatory cells

Zhuoxiao Cao, Akm Khyrul Wara, Basak Idi, Xinghui Sun, René R.S. Packard, Fehim Esen, Christopher J. Stapleton, Malayannan Subramaniam, Karsten Kretschmer, Irina Apostolou, Harald von Boehmer, Göran K. Hansson, Thomas C. Spelsberg, Peter Libby, Mark W. Feinberg

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

CD4+CD25+ regulatory T cells (T regs) play a major role in the maintenance of self-tolerance and immune suppression, although the mechanisms controlling T reg development and suppressor function remain incompletely understood. Herein, we provide evidence that Kruppel-like factor 10 (KLF10/TIEG1) constitutes an important regulator of T regulatory cell suppressor function and CD4+CD25+ T cell activation through distinct mechanisms involving transforming growth factor (TGF)-β1 and Foxp3. KLF10 overexpressing CD4+CD25- T cells induced both TGF-β1 and Foxp3 expression, an effect associated with reduced T-Bet (Th1 marker) and Gata3 (Th2 marker) mRNA expression. Consistently, KLF10-/- CD4+CD25- T cells have enhanced differentiation along both Th1 and Th2 pathways and elaborate higher levels of Th1 and Th2 cytokines. Furthermore, KLF10-/- CD4+CD25- T cell effectors cannot be appropriately suppressed by wild-type T regs. Surprisingly, KLF10-/ - T reg cells have reduced suppressor function, independent of Foxp3 expression, with decreased expression and elaboration of TGF-β1, an effect completely rescued by exogenous treatment with TGF-β1. Mechanistic studies demonstrate that in response to TGF-β1, KLF10 can transactivate both TGF-β1 and Foxp3 promoters, implicating KLF10 in a positive feedback loop that may promote cell-intrinsic control of T cell activation. Finally, KLF10-/- CD4+CD25- T cells promoted atherosclerosis by ∼2-fold in ApoE-/-/scid/scid mice with increased leukocyte accumulation and peripheral pro-inflammatory cytokines. Thus, KLF10 is a critical regulator in the transcriptional network controlling TGF-β1 in both CD4+CD25- T cells and T regs and plays an important role in regulating atherosclerotic lesion formation in mice.

Original languageEnglish (US)
Pages (from-to)24914-24924
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number37
DOIs
StatePublished - Sep 11 2009

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cao, Z., Wara, A. K., Idi, B., Sun, X., Packard, R. R. S., Esen, F., Stapleton, C. J., Subramaniam, M., Kretschmer, K., Apostolou, I., von Boehmer, H., Hansson, G. K., Spelsberg, T. C., Libby, P., & Feinberg, M. W. (2009). Kruppel-like factor KLF10 targets transforming growth factor-β1 to regulate CD4+ CD25- T cells and T regulatory cells. Journal of Biological Chemistry, 284(37), 24914-24924. https://doi.org/10.1074/jbc.M109.000059