Kruppel-like Factor KLF10 Targets Transforming Growth Factor-beta 1 to Regulate CD4(+)CD25(-) T Cells and T Regulatory Cells

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Cao Z., Wara A. K. , Icli B., Sun X., Packard R. R. S. , Esen F., ...More

JOURNAL OF BIOLOGICAL CHEMISTRY, vol.284, no.37, pp.24914-24924, 2009 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 284 Issue: 37
  • Publication Date: 2009
  • Doi Number: 10.1074/jbc.m109.000059
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.24914-24924


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)-beta 1 and Foxp3. KLF10 overexpressing CD4(+)CD25(-) T cells induced both TGF-beta 1 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-beta 1, an effect completely rescued by exogenous treatment with TGF-beta 1. Mechanistic studies demonstrate that in response to TGF-beta 1, KLF10 can transactivate both TGF-beta 1 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 similar to 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-beta 1 in both CD4(+)CD25(-) T cells and T regs and plays an important role in regulating atherosclerotic lesion formation in mice.