共 62 条
Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25- T Cells and T Regulatory Cells
被引:85
作者:
Cao, Zhuoxiao
[1
]
Wara, Akm Khyrul
[1
]
Icli, Basak
[1
]
Sun, Xinghui
[1
]
Packard, Rene R. S.
[1
]
Esen, Fehim
[1
]
Stapleton, Christopher J.
[1
,6
]
Subramaniam, Malayannan
[2
]
Kretschmer, Karsten
[3
]
Apostolou, Irina
[3
]
von Boehmer, Harald
[3
]
Hansson, Goran K.
[4
,5
]
Spelsberg, Thomas C.
[2
]
Libby, Peter
[1
]
Feinberg, Mark W.
[1
]
机构:
[1] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp,Cardiovasc Div, Boston, MA 02115 USA
[2] Mayo Clin, Dept Biochem & Mol Biol, Coll Med, Rochester, MN 55905 USA
[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA
[4] Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden
[5] Karolinska Inst, Dept Med, SE-17176 Stockholm, Sweden
[6] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA 02115 USA
基金:
瑞典研究理事会;
美国国家卫生研究院;
关键词:
GROWTH-FACTOR-BETA;
TRANSCRIPTION FACTOR FOXP3;
TGF-BETA;
CUTTING EDGE;
TRANSPLANT ARTERIOSCLEROSIS;
ACCELERATES ATHEROSCLEROSIS;
AGGRAVATES ATHEROSCLEROSIS;
VASCULAR INFLAMMATION;
PERIPHERAL TOLERANCE;
FACTOR EKLF;
D O I:
10.1074/jbc.M109.000059
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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.
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页码:24914 / 24924
页数:11
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