TY - JOUR
T1 - Kruppel-like factor KLF10 targets transforming growth factor-β1 to regulate CD4+ CD25- T cells and T regulatory cells
AU - Cao, Zhuoxiao
AU - Wara, Akm Khyrul
AU - Idi, Basak
AU - Sun, Xinghui
AU - Packard, René R.S.
AU - Esen, Fehim
AU - Stapleton, Christopher J.
AU - Subramaniam, Malayannan
AU - Kretschmer, Karsten
AU - Apostolou, Irina
AU - von Boehmer, Harald
AU - Hansson, Göran K.
AU - Spelsberg, Thomas C.
AU - Libby, Peter
AU - Feinberg, Mark W.
PY - 2009/9/11
Y1 - 2009/9/11
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.000059
DO - 10.1074/jbc.M109.000059
M3 - Article
C2 - 19602726
AN - SCOPUS:69949187036
SN - 0021-9258
VL - 284
SP - 24914
EP - 24924
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -