Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25- T Cells and T Regulatory Cells.

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 (KLF1O/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 (Thi 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 ioop 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. [ABSTRACT FROM AUTHOR]